Selenophene anti-tumor agents

ABSTRACT

Novel selenophene compounds useful as anti-tumor agents are described. Preferred compounds include compounds of formula I:  
                 
 
wherein R 1  and R 2  are independently selected from the group consisting of  
                 
 
H, CHO, CH 2 OH, and CH 2 NH 2 ; and 
         X and Y are independently selected from the group consisting of Se, S, O, NCH 3 , and NH. Pharmaceutical compositions and a method for treating patients having tumors utilizing the disclosed selenophene compounds are also described.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/103,991, filed on Apr. 12, 2005, now abandoned, which is a divisionalapplication of U.S. patent application Ser. No. 10/658,175, filed onSep. 9, 2003, which is a divisional application of U.S. patentapplication Ser. No. 10/061,480, filed on Feb. 1, 2002, now issued asU.S. Pat. No. 6,620,804, which is a continuation application of U.S.patent application Ser. No. 09/180,514, filed on Nov. 11, 1998, nowabandoned, which is a U.S. national application of internationalapplication serial No. PCT/US97/09717, filed on Jun. 3, 1997, whichclaims priority to U.S. Provisional Patent Application Ser. No.60/019,095, filed on Jun. 3, 1996, the disclosures of each of which areincorporated herein by reference.

GOVERNMENT RIGHTS

This invention was made with United States Government support underGrant No. UO1 CA50743, awarded by the National Cancer Institute. TheUnited States Government has certain rights in the invention.

FIELD OF THE INVENTION

The present invention relates to compositions and a method for treatinga patient having a tumor. More specifically, the present inventionrelates to the treatment of such patients with an effective amount of aselenophene derivative.

BACKGROUND AND SUMMARY OF THE INVENTION

The control and cure of cancer represents one of our most challenginghealth problems. The treatment of cancer can be approached by severalmodes of therapy including surgery, radiation, chemotherapy or acombination of any of these treatments. Chemotherapy continues to be anindispensable therapy for inoperable or metastatic forms of the disease.

The selection of natural compounds, or the synthesis of new compoundshaving effective anticancer activity is complicated by the still limitedknowledge of cancer cell biology and biochemistry. Therefore,development of new effective anti-tumor agents will remain heavilydependent on screening compounds to discover novel compounds havingcytotoxic activity. Preferably, such compounds exhibit enhancedcytotoxicity against tumor cells relative to their cytotoxicity tonormal cells.

The success of novel antitumor drug development programs is dependent onthe initial identification of antitumor agents. Thus the discovery ofantitumor agents requires the systematic screening of a large number ofnatural products and synthetic compounds.

The mouse L1210 leukemia cell line was initially the preferred modelsystem used for screening natural compounds for antitumor activity.However, the P388 murine leukemia system was found to be more sensitiveand predictive than L1210 leukemia system, and has been used as primaryscreen during the past decade. Systematic screening for compoundsexhibiting toxicity to these two leukemia cell lines has resulted in theisolation of a large number of active natural products. However, theanticancer activities of these compounds were predominantly in leukemia,lymphoma and a few rare tumors. Low clinical efficacy, or the lack ofclinical efficacy of known chemotherapeutics against slower growingsolid tumors, is a serious concern.

It has been recognized that the use of a single antileukemia screeningsystem could bias the end results and lead to the isolation of compoundsonly active in the treatment of fast growing tumors. In addition, theuse of a single antileukemia screening system may not detect novelcompounds with high specificities for particular cell lines. It is alsolikely that many novel compounds with possible anti-tumor activity haveremained undetected by the less sensitive in vivo models due to the lowconcentrations at which many active natural products occur.

Considering the diversity of tumors in terms of cell type, morphology,growth rate and other cellular characteristics, the U.S. National CancerInstitute (NCI) has developed a “disease-oriented” approach to antitumoractivity screening (M. R. Boyd, in “Principle of Practice of Oncology”J. T. Devita, S. Hellman, S. A. Rosenberg (Eds.) Vol. 3, PPO Update, No.10, 1989). This in vitro prescreening system is based on the measurementof antitumor cytotoxicity against human tumor cell line panelsconsisting of approximately 60 cell lines of major human tumors(including leukemia and slower growing tumor cells such as lung, colon,breast, skin, kidney, etc.). The most important advantage of the new invitro screening panels is the opportunity to identify compounds that areselectively more cytotoxic to cells of slowly growing solid tumors thanto rapidly growing leukemia cells.

The cytotoxicity profile of the NCI human tumor cell panels displays thetumor specificity of a given compound, however the assay does not assessthe toxicity of that compound to normal human cells. Accordingly asecond bioassay is utilized to measure the selective cytotoxicityagainst certain types of tumor cells verses normal human cells.

The growth and differentiation of cells are regulated by signalingcascades induced by various mitogenic proteins (J. Kuijan and B. L.Taylor, “Signal Transduction,” Academic Press, New York, N.Y. 1994) thatoften are encoded by proto-oncogenes. The overexpression, amplificationor mutation of the oncoprotein is critically involved in the initiation,progression and metastasis of malignant cells (R. A. Weinberg,“Oncogenes and the Molecular Origins of Cancer,” Cold Spring HarborLaboratory Press, Cold Spring Harbor, N.Y., 1989). Many oncoproteinsalter normal cellular growth regulation by modulating the intracellularsignaling pathways from the membrane to the nucleus. Therefore, cancermay be considered as a disease of cellular signal transduction, whichpresents a novel approach for anticancer therapy. One of the criticalenzymes involved in the oncoprotein signal transduction is proteinkinase C (U. Nishizuka, Nature, 308, 693, 1984 and Science, 233, 305,1986). Thus, the determination of a compound's ability to inhibitprotein kinase C activity has become a good prognostic for discoveringnovel anticancer agents (A. Basu, Pharmac Ther, 59, 257, 1993).Furthermore it is anticipated that the selenophene compounds willdemonstrate selectivity for certain class members of protein kinases,including protein kinase C. Inhibition of specific classes of proteinkinases will allow the treatment of other diseases associated withdefects in signaling transduction.

Selenophenes are selenium containing heterocyclic compounds that areanalogs of naturally occurring thiophene, furan and pyrrole compounds.Selenophenes have been found to be effective antitumor agents, andexhibit enhanced cytotoxicity against slow growing tumor cells;selective cytotoxicity against human renal, ovarian tumor cells, andskin tumor cells; and exhibit inhibition of protein kinase C.

In accordance with this invention there is provided a method for thetreatment of cancer which utilizes selenophene compounds of the formulaI:

wherein R₁ and R₂ are independently selected from the group consistingof;

H, CHO, CH₂OH, and CH₂NH₂;

X and Y are independently selected from the group consisting of Se, S,O, NCH₃ and NH;

R₃, R₄, R₅, and R₆ are independently selected from the group consistingof H, CHO, CH₂OH, and CH₂NH₂; cyclodextrin complexes of such compounds;and when R₃, R₄, R₅, or R₆ is CH₂NH₂, the pharmaceutically acceptablesalt of the compound represented thereby.

Further in accordance with this invention there are provided novelcytotoxic compounds of the above formula and chemotherapeuticpharmaceutical compositions containing said compounds in anti-tumoreffective amounts.

Additional objects, features, and advantages of the invention willbecome apparent to those skilled in the art upon consideration of thefollowing detailed description of preferred embodiments exemplifying thebest mode of the invention as presently perceived.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to selenophene compounds, theirpharmaceutical compositions and methods utilizing suchcompounds/compositions for treating patients having tumor. Theselenophene compounds are effective antitumor agents against slowgrowing tumors, and generally have been found to exhibit high selectivecytotoxicity for individual tumor cell lines.

The present selenophene compounds are readily prepared usingart-recognized chemical synthesis procedures as exemplified in Example 1and in Examples 3-8. This invention is further envisioned from thechemical concept on the basis of a coherent design as shown in Scheme 3in Example 2. This chemical concept provides the foundation forconceiving the preparation and utility of numerous “hybrid” selenophenecompounds containing other related five-membered heterocycles, such asfuran, thiophene, and pyrrole, and their analogs. Moreover, the practiceof this chemical concept is substantiated by Example 2 and by Examples9-33. The anticancer utility of these hybrid selenophene compounds ismanifested by (a) selective cytotoxicity for human renal carcinoma cellsin comparison to normal human renal cells (Table 1), (b) antitumorcytotoxicity against a variety of human tumor cells (Example 53), (c) invivo antitumor activity against human lung tumor (Example 54), and (d)inhibition of protein kinase C activity (Table 2).

In corroboration with the above chemical concept, a versatile,alternative synthetic design is further conceived for the preparation ofrelevant “hybrid” selenophene compounds as in the scheme shown inExample 34. The practice of this synthetic design is supported byExamples 34-50. The anticancer utility of these hybrid selenophenecompounds is indicated by (a) selective cytotoxicity for human renalcarcinoma cells in comparison to normal human renal cells (Table 1), (b)antitumor cytotoxicity against a variety of human tumor cells (Example53), (c) in vivo antitumor activity against human lung tumor (Example54) and (d) inhibition of protein kinase C (Table 2).

The compounds of the present invention are selenophene compounds of theformula I:

wherein R₁ and R₂ are independently selected from the group consistingof;

H, CHO, CH₂OH, and CH₂NH₂;

X and Y are independently selected from the group consisting of Se, S,O, and NR;

R is H or C₁-C₇ alkyl;

R₃, R₄, R₅, and R₆ are independently selected from the group consistingof nitro, amino, alkoxy, cyano, chloro, bromo, iodo, C₁-C₇ alkyl orhaloalkyl, C₁-C₇ alkenyl or haloalkenyl, C₁-C₄ alkanoyloxy methyl,CH₂OR₇, COR₈, CH₂NR₉R₁₀, CH(OR₇)R₁₁, CH═CR₁₂R₁₃, CH═NR₁₄, CH₂SC(NH)NH₂and C═CR₁₅ wherein:

R₇ is H, CO(CH₂)₂CO₂H, (CH₂)₂OCH₃, C₁-C₄ alkyl or COC₁-C₁₇ alkyl;

R₈ is H or C₁-C₇ alkyl;

R₉ and R₁₀ are independently H, CN, C₁-C₄ alkyl, or mono- ordi-hydroxyC₂-C₄ alkyl;

R₁₁ is C₁-C₇ alkyl, or C₁-C₇ alkenyl;

R₁₂ and R₁₃ are independently H, C₁-C₇ alkyl, COOR₈, CN, CH(OR₇)COOR₈,Br, CO-thienyl, COC₆H₄OH(p);

R₁₄ is NHR₇ or OR₈;

R₁₅ is COOR₈, CH(OR₇)CH₂OR₁₆ or CH(OCOC₁-C₄ alkyl)CH₂OR₈;

R₁₆ is H, COCH₂CH₂CO₂H, or COC₁-C₇ alkyl;

cyclodextrin complexes of such compound and when R₃, R₄, R₅ or R₆ isCH₂NR₆R₇, the pharmaceutically acceptable salt of the compoundrepresented thereby.

In one preferred embodiment of this invention there is providedanti-tumor selenophenes of the above formula I,wherein R₂ is:

X and Y are independently selected from the group consisting of S, Se,and NH;

R₁, R₃, and R₆ are H; and

R₅ is selected from the group consisting of CHO or CH₂OH; andcyclodextrin complexes of such compounds. These compounds have beendemonstrated to exhibit cytotoxic selectivity against transformed humancells (See Table 1).

In another preferred embodiment of this invention there is providedanti-tumor selenophenes of the above formula I wherein R₁ is:

X and Y are independently selected from the group consisting of S, Se,and NH;

R₂, R₃, and R₆ are H;

R₅ is selected from the group consisting of CHO or CH₂OH; andcyclodextrin complexes of such compounds.

Other preferred compounds in accordance with this invention areselenophenes of formula I:

wherein R₁ and R₂ are independently selected from the group consistingof;

H, CHO, CH₂OH, and CH₂NH₂;

X and Y are independently selected from the group consisting of Se, S,O, NCH₃, and NH;

R₃, R₄, R₅, and R₆ are independently selected from the group consistingof H, CHO, CH₂OH, and CH₂NH₂; cyclodextrin complexes of such compounds;and when R₂ or R₃ is CH₂NH₂, the pharmaceutically acceptable salt of thecompound represented thereby; with the proviso, that when R₂ is:

R₁ is other than

and when R₁ is

R₂ is other than

In accordance with another embodiment of the present invention novelintermediates of Formula II are also provided:

wherein W is selected from the group consisting of N(CH₃)₂ and

and X and Y are independently selected from the group consisting of Se,S, O, NCH₃ and NH.

One aspect of the present invention is a method of preparing thecompounds of Formula I through an intermediate compound of the formula:

in accordance with the general methods of schemes 1-4 as describedhereinbelow,wherein X and Y are independently selected from the group consisting ofSe, S, O, NCH₃, and NH.

The selenophene compounds of this invention are readily formulated intopharmaceutical compositions, also within the scope of this invention,for use in the presently described method for treatment of patientshaving tumors. In one preferred embodiment of this invention, thepharmaceutical composition comprises an anti-tumor effective amount of aselenophene compound of formula I:

wherein R₁ and R₂ are independently selected from the group consistingof;

H, CHO, CH₂OH, and CH₂NH₂;

X and Y are independently selected from the group consisting of Se, S,O, and NR, wherein R is H or C₁-C₇ alkyl;

R₃, R₄, R₅, and R₆ are independently selected from the group consistingof nitro, amino, alkoxy, cyano, chloro, bromo, iodo, C₁-C₇ alkyl orhaloalkyl, C₁-C₇ alkenyl or haloalkenyl, C₁-C₄ alkanoyloxy methyl,CH₂OR₇, COR₈, CH₂NR₉R₁₀, CH(OR₇)R₁₁, CH═CR₁₂R₁₃, CH═NR₁₄, CH₂SC(NH)NH₂,and C≡CR₁₅ wherein:

R₇ is H, CO(CH₂)₂CO₂H, (CH₂)₂OCH₃, C₁-C₄ alkyl or COC₁-C₁₇ alkyl;

R₈ is H or C₁-C₇ alkyl;

R₉ and R₁₀ are independently H, CN, C₁-C₄ alkyl, or mono- ordi-hydroxyC₂-C₄ alkyl;

R₁₁ is C₁-C₇ alkyl, or C₁-C₇ alkenyl;

R₁₂ and R₁₃ are independently H, C₁-C₇ alkyl, COOR₈, CN, CH(OR₇)COOR₈,Br, CO-thienyl, COC₆H₄OH(p);

R₁₄ is NHR₇ or OR₈;

R₁₅ is COOR₈, CH(OR₇)CH₂OR₁₆ or CH(OCOC₁-C₄ alkyl)CH₂OR₈;

R₁₆ is H, COCH₂CH₂CO₂H, or COC₁-C₇ alkyl;

cyclodextrin complexes of such compound and

when R₃, R₄, R₅, or R₆ is CH₂NR₆R₇, the pharmaceutically acceptable saltof the compound represented thereby, and a pharmaceutically acceptablecarrier.

Another pharmaceutical composition within the scope of this inventioncomprises an anti-tumor effective amount of a selenophene compound ofthe formula I:

wherein R₁ and R₂ are independently selected from the group consistingof;

H, CHO, CH₂OH, and CH₂NH₂;

X and Y are independently selected from the group consisting of Se, S,O, NCH₃ and NH;

R₃, R₄, and R₆ are H;

R₅ is selected from the group consisting of H, CHO, CH₂OH and CH₂NH₂;cyclodextrin complexes of such compounds; and when R₃, R₄, R₅, or R₆ isCH₂NH₂, the pharmaceutically acceptable salt of the compound representedthereby; with the proviso, that when R₂ is

R₁ is other than

and when R₁ is

R₂ is other than

and a pharmaceutically acceptable carrier.

The present compounds are readily prepared using art-recognizedchemical-synthesis procedures as exemplified hereinbelow.

The cytotoxic activity of the present selenophene compounds have beenmeasured utilizing two different assays or screens. The first screenmeasures the cytotoxicity against a panel of sixty different human tumorcell lines. This assay provides data regarding the general cytotoxicityof an individual compound. In particular this type of assay is useful inidentifying compounds which have enhanced cytotoxic activity againstslow growing tumors as compared to faster growing tumor cells such asleukemia tumor cell lines. The identification of such compounds iscritical since previously identified antitumor agents have low cytotoxicactivity against slower growing tumors. The specificity of a compoundfor a limited number of tumor cell lines also indicates that such acompound will likely be less cytotoxic to normal cells. The specificityof a cytotoxic compound for tumor cell lines relative to normal cells isan important characteristic of an effective antitumor agent.

Antitumor cytotoxicity data generated from the National Cancer Institutehuman tumor cell panels can also be expressed in a graphic pattern (meangraph) to display differential cell growth inhibition (K. D. Paull, R.H. Shoemaker, L. Hodes, A. Monks, D. A. Scudiero, L. Rubinstein, J.Plowman and M. R. Boyd, J. Natl. Cancer Inst., 81, 1088, (1989)). In themean graph, the arithmetic mean of the logarithm of the GI₅₀ (50% growthinhibition), TGI (total growth inhibition) or LC₅₀ (50% lethalconcentration) values is used as an anchor point. Relative cytotoxicityis displayed by projecting bars to the right or left of the mean,depending on whether cell sensitivity to a test compound is more or lessthan average. The length of a bar is indicative of differentialcytotoxicity against a specific type of tumor cells or tumor panels.

In a second assay, the cytotoxic selectivity is assessed by comparingcompound cytotoxicity against human renal carcinoma cells (A-498),ras-transformed human bronchial epithelial cells (TBE) and normal humanrenal cells (RPTEC). IC₅₀ values were compared between treated TBE cellsand RPTEC cells and the selective cytotoxicity index (SCI) wasdetermined [SCI=GI₅₀(RPTEC)/GI₅₀ (A-498)].

The antitumor cytotoxicity of the selenophene compounds tested in thosein vitro assays was measured by a microculture assay using either a3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) orsulforhodamine B (SRB) based assay. [M. R. Boyd in “Principles andPractices of Oncology,” V. T. DeVita, Jr.]. The experiments wereconducted at Purdue University in 96-well microtiter plates and thecytotoxic effects of the selenophene compounds on those cells weremeasured by cell count using a Coulter Z. F. counter (Hialeah, Fla.).The results are expressed as GI₅₀, the concentration of drug at whichcell numbers are reduced to 50% of control cell culture (T. C. K. Chan,C. J. Chang, N. M. Koonchanok and R. L. Geahlen, Biochem. Biophys. Res.Commun., 193, 1152, (1993); S. Hellman and S. A. Rosenberg (Eds.), Vol.3, PPO Updates, Number 10, (1989)).

This in vitro microculture assay has an advantage over in vivo assays inthat results are obtained within a week as opposed to several months.The MTT assay is based on the production of a dark blue formazan productby dehydrogenase in the mitochondria of live tumor cells after exposureto drug for 6 days (M. C. Alley, D. A. Scudiero, A. Monks, M. L. Hursey,M. J. Czerwinski, D. L. Fine, B. J. Abbott, J. G. Mayo, R. H. Shoemakerand M. R. Boyd, Cancer Res., 48, 589, (1988)). Thus, only live cells arestained and can be measured at 570 nm. The SRB assay is based on thebinding of the anionic group to the basic amino acid residues ofcellular proteins after exposure of tumor cells to drug for 2 days (P.Skehan, R. Storeng, D. Scudiero, A. Monks, J. McMahon, D. Vistica, J. T.Warren, H. Bohesch, S. Kenney and M. R. Boyd, J. Nat. Cancer Inst., 82,1107, (1990)). Thus, the total protein can be measured at 564 nm.Antitumor cytotoxicity is reported as GI₅₀, effect drug dose at whichcell growth is retarded to 50% of control culture of tumor cells. Theactive compounds are defined as those compounds having GI₅₀ values thatare less than 10⁻⁴ M or 10 μg/mL.

The data presented in Table 1 illustrates that selenophenes generallyexhibit greater cytotoxicity for human renal carcinoma cells incomparison to the normal human cells. The data of Table 1 demonstratesthe selective cytotoxicity of various selenophene compounds againsthuman renal carcinoma and ras-oncogene transformed human bronchialepithelial cells [in GI₅₀(μg/mL)]. The following abbreviations are usedfor the tested cell lines:

RPTEC: normal human renal cells

A-498: human renal carcinoma

TBE: ras-transformed human bronchial epithelial cells

SCI: selectively cytotoxicity index=GI₅₀ (RPTEC)/GI₅₀ (A-498) TABLE 1NSC GI₅₀(μg/ml) Number RPTEC A-498 TBE SCI 674973 4 × 10⁰ 3 × 10⁰ 4 ×10⁰ 1 675246 1 × 10⁻¹ 3 × 10⁻⁶ 3 × 10⁻³ >1000 3 × 10⁻² 3 × 10⁻⁶ 2 ×10⁻³ >1000 675247 2 × 10⁻¹ 7 × 10⁻⁵ 3 × 10¹ >1000 8 × 10⁰ 2 × 10⁻⁶ 2 ×10¹ >1000 676628 4 × 10² 8 × 10¹ 1 × 10² 5 676632 2 × 10⁻³ 3 × 10⁻⁷  <10⁻³ >1000 3 × 10⁻⁴ 2 × 10⁻⁷ 2 × 10⁻⁴ >1000 675347 2 × 10¹ 3 × 10¹ 1× 10¹ <1 675344   <10⁻² 3 × 10⁻⁷   <10⁻² >1000 1 × 10⁻⁴ 6 × 10⁻⁸ 7 ×10⁻⁶ >1000 676633 2 × 10¹ 1 × 10² 1 × 10¹ <1 676634 1 × 10¹ 6 × 10⁻⁴ 3 ×10⁻⁴ >1000 4 × 10⁻¹ 3 × 10⁻³ 6 × 10⁻³ >100 676635 2 × 10⁰   <10⁻³ 2 ×10¹ >1000 123127 5 × 10⁻² 5 × 10⁻² 3 × 10² 1 NSC Number Structure 674973

675246

675247

676628

676632

675347

675344

676633

676634

676635

123127 AdriamycinRPTEC: normal human renal cellsA-498: human renal carcinomaTBE: ras-transformed human bronchial epithelial cellsSCI: selectively cytotoxicity index = GI₅₀(RPTEC)/GI₅₀(A-498)

The present invention further provides pharmaceutical formulationscomprising an effective amount of a selenophene compound for treating apatient having a tumor. As used herein, an effective amount of theselenophene compound is defined as the amount of the compound which,upon administration to a patient, inhibits growth of tumor cells, killsmalignant cells, reduces the volume or size of the tumors or eliminatesthe tumor entirely in the treated patient.

The effective amount to be administered to a patient is typically basedon body surface area, patient weight, and patient condition. Theinterrelationship of dosages for animals and humans (based on milligramsper meter squared of body surface) is described by Freireich, E. J., etal., Cancer Chemother Rep 50 (4): 219 (1966). Body surface area may beapproximately determined from patient height and weight (see e.g.,Scientific Tables, Geigy Pharmaceuticals, Ardley, N.Y. pages 537-538(1970)). An effective amount of the selenophene compounds in the presentinvention can range from about 5 mg/kg to about 100 mg/kg, morepreferably from about 0.25 mg/kg to about 50 mg/kg, and most preferablyabout 0.1 to about 10 mg/kg.

Effective doses will also vary, as recognized by those skilled in theart, dependant on route of administration, excipient usage and thepossibility of co-usage with other therapeutic treatments includingother anti-tumor agents, and radiation therapy.

The pharmaceutical formulation may be administered via the parenteralroute, including subcutaneously, intraperitoneally, intramuscularly andintravenously. Examples of parenteral dosage forms include aqueoussolutions of the active agent, in a isotonic saline, 5% glucose or otherwell-known pharmaceutically acceptable liquid carrier. In one preferredaspect of the present embodiment, the selenophene compound is dissolvedin a saline solution containing 5% of dimethyl sulfoxide and 10%Cremphor EL (Sigma Chemical Company). Additional solubilizing agentssuch as cyclodextrins, which form specific, more soluble complexes withthe present selenophene compounds, or other solubilizing agentswell-known to those familiar with the art, can be utilized aspharmaceutical excipients for delivery of the selenophene compounds.

The present compound can also be formulated into dosage forms for otherroutes of administration utilizing well-known methods. Thepharmaceutical compositions can be formulated, for example, in dosageforms for oral administration in a capsule, a gel seal or a tablet.Capsules may comprise any well-known pharmaceutically acceptablematerial such as gelatin or cellulose derivatives. Tablets may beformulated in accordance with conventional procedure by compressingmixtures of the active polythiophene and solid carriers, and lubricantswell-known to those familiar with the art. Examples of solid carriersinclude starch, sugar, bentonite. The compounds of the present inventioncan also be administered in a form of a hard shell tablet or capsulecontaining, for example, lactose or mannitol as a binder andconventional fillers and tableting agents.

The following examples are provided to illustrate various embodiments ofApplicants' invention, and are not intended to in any way limit thescope of the invention as set forth in this specification and appendedclaims.

EXAMPLE 1 Synthesis of α-Terselenophenes

A two-step total synthesis of α-terselenophene from selenophene (AldrichChemical Co.) has been developed (see Scheme 1).

Bis(tricyclohexyltin)selenide can be prepared from tricyclohexyltinchloride (Aldrich Chemical Co.) and sodium selenide (Alfa Chemical Co.).The functional group can be introduced through selective α-formulationusing lithium diisopropylamide (LDA) and dimethylformamide (DMF), whichcan then be sequentially converted into hydroxylmethyl and aminomethylfunctional groups. These functional groups can provide required startingpoints for further chemical modifications, see Scheme 2 as follows:

EXAMPLE 2 Synthesis of Hybrid α-Terselenophenes

The synthetic strategy designed for the preparation of α-terselenophenecan be readily modified for the synthesis of numerous “hybrid”α-selenophenes containing other five-membered heterocycles (see Scheme3).

Wherein X, and Y are selected from the group consisting of Se, O, S,NCH₃, and NH₂; and Z is selected from the group consisting of Se, S,NCH₃, and NH₂. Various functional groups can be introduced using theapproaches outlined in the synthesis of α-terselenophenes (see Scheme2).

EXAMPLE 3 Preparation of 1,4-diselenophene-1,4-diketone.

A CH₂Cl₂ solution containing selenophene (5 g) and succinyl chloride (2g) was added dropwise to an anhydrous CH₂Cl₂ solution (60 mL) containingAlCl₃ (5 g) under N₂ at 0° C. The reaction mixture was stirred at 0° C.for 1 h, slowly warmed to room temperature, and stirred for 4 h at roomtemperature. The reaction mixture was poured into a beaker containingice. Ethyl acetate (200 mL) was added and the organic layer wasseparated out using a separatory funnel. The aqueous layer was backwashed with ethyl acetate (2×100 mL). The combined organic layer waswashed with H₂O (2×300 mL). The organic layer was collected, dried overMgSO₄, filtered, and the solvent was removed under vacuum. The residuewas chromatographed over silica gel using (10:1) hexanes/ethyl acetateto afford the product in 25% yield.

EXAMPLE 4 Preparation of 2,2′:5′,2″-terselenophene

A BCl₃ solution (1.0 M solution in hexanes, 580 μL) was added dropwiseto an anhydrous toluene solution (5 mL) containing1,4-diselenophene-1,4-diketone (100 mg) andbis(tricyclohexyltin)selenide (520 mg) under N₂ at room temperature. Thesolution was refluxed for 30 min and cooled to room temperature. Thereaction solution was diluted with ethyl acetate (100 mL) and washedwith H₂O (2×100 mL). The organic layer was separated, dried over MgSO₄,filtered, and the solvent was removed under vacuum. The residue waschromatographed over silica gel using hexanes to afford2,2′:5′2″-terselenophene in 80% yield.

EXAMPLE 5 Preparation of 2-formyl-5,2′:5′,2″-terselenophene

LDA (1.0 M solution in THF, 310 μL) was added to an anhydrous THFsolution (4 mL) containing 2,2′:5′,2″-terselenophene (100 mg) under N₂at −78° C. The solution was stirred at −78° C. for 3 h, anhydrous DMF (1mL) was added, stirred at −78° C. for 1 h, and slowly warmed to roomtemperature. The reaction solution was diluted with ethyl acetate (100mL) and washed with H₂O (4×100 mL). The organic layer was separated,dried over MgSO₄, filtered, and the solvent was removed under vacuum.The residue was chromatographed over silica gel using CH₂Cl₂ to afford2-formyl-5,2′:5′,2″-terselenophene in 75% yield.

EXAMPLE 6 Preparation of 2,5″-diformyl-5,2′:5′,2″-terselenophene

LDA (1.0 M solution in THF, 1.0 mL) was added to an anhydrous THFsolution (4 mL) containing 2,2′:5′,2″-terselenophene (100 mg) under N₂at −78° C. The solution was stirred at −78° C. for 3 h, anhydrous DMF (2mL) was added, stirred at −78° C. for 1 h, and slowly warmed to roomtemperature. The reaction solution was diluted with ethyl acetate (100mL) and washed with H₂O (4×100 mL). The organic layer was separated,dried over MgSO₄, filtered, and the solvent was removed under vacuum.The residue was chromatographed over silica gel using (5:1) CH₂Cl₂/ethylacetate to afford 2,5″-diformyl-5,2′:5′,2″-terselenophene in 75% yield.

EXAMPLE 7 Preparation of 2-hydroxymethyl-5,2′:5′,2″-terselenophene

NaBH₄ (10 mg) was added to a THF solution (2 mL)2-formyl-5,2′:5′,2″-terselenophene (15 mg) and stirred at roomtemperature for 2 h. The reaction solution was diluted with ethylacetate (50 mL), washed with 2N HCl (5 mL), and then washed with H₂O(3×50 mL). The organic layer was separated, dried over MgSO₄, filtered,and the solvent was removed under vacuum. The residue waschromatographed over silica gel using (2:1) hexanes/ethyl acetate toafford 2-hydroxymethyl-5,2′:5′,2″-terselenophene in 98% yield.

EXAMPLE 8 Preparation of 2,5″-dihydroxymethyl-5,2′:5′,2″-terselenophene

NaBH₄ (10 mg) was added to a THF solution (2 mL) containing2,5″-diformyl-5,2′:5′,2″-terselenophene (15 mg) and stirred at roomtemperature for 5 h. The reaction solution was diluted with ethylacetate (50 mL), washed with 2N HCl (5 mL), and washed with H₂O (3×100mL). The organic layer was separated, dried over MgSO₄, filtered, andthe solvent was removed under vacuum. The residue was chromatographedover silica gel using (1:1) hexanes/ethyl acetate to afford2,5″-dihydroxymethyl-5,2′:5′,2″-terselenophene in 98% yield.

EXAMPLE 9 Preparation of 2,4-diselenophenylfuran

d-10-Camphorsulfonic acid (2 g) was added to an ethanolic solution (15mL) containing 2′,2″-diselenophene-1,4-diketone (100 mg) and refluxedfor 2 days. The reaction solution was diluted with ethyl acetate (100mL) and washed with H₂O (3×100 mL). The organic layer was separated,dried over MgSO₄, filtered, and the solvent was removed under vacuum.The residue was chromatographed over silica gel using (10:1)hexanes/ethyl acetate to afford 2,2′:5,2″-diselenophenylfuran in 90%yield.

EXAMPLE 10 Preparation of 5′-formyl-2,2′:5,2″-diselenophenylfuran

LDA (1 molar solution in THF, 350 μL) was added to an anhydrous THFsolution (4 mL) containing 2,2′:5,2″-diselenophenylfuran (100 mg) underN₂ at −78° C. The solution was stirred at −78° C. for 3 h, anhydrous DMF(excess) was added, stirred at −78° C. for 1 h, and slowly warmed toroom temperature. The reaction solution was diluted with ethyl acetate(100 mL) and washed with H₂O (3×100 mL). The organic layer wasseparated, dried over MgSO₄, filtered, and the solvent was removed undervacuum. The residue was chromatographed over silica gel using (4:1)hexanes/ethyl acetate to afford 5′-formyl-2,2′:5,2″-diselenophenylfuran.

EXAMPLE 11 Preparation of 5′,5″-diformyl-2,2′:5,2″-diselenophenylfuran

LDA (1 molar solution in THF, 1 mL) was added to an anhydrous THFsolution (4 mL) containing 2,2′:5,2″-diselenophenylfuran (100 mg) underN₂ at −78° C. The solution was stirred at −78° C. for 3 h, anhydrous DMF(excess) was added, stirred at −78° C. for 1 h, and slowly warmed toroom temperature. The reaction solution was diluted with ethyl acetate(100 mL) and washed with H₂O (3×100 mL). The organic layer wasseparated, dried over MgSO₄, filtered, and the solvent was removed undervacuum. The residue was chromatographed over silica gel using (4:1)hexanes/ethyl acetate to afford5,5″-diformyl-2,2′:5,2″-diselenophenylfuran.

EXAMPLE 12 Preparation of 5′-hydroxymethyl-2,2′:5,2″-diselenophenylfuran

NaBH₄ (excess) was added to a THF solution (2 mL) containing5′-formyl-2,2′:5,2″-diselenophenylfuran (15 mg) and stirred at roomtemperature for 5 h. The reaction solution was diluted with ethylacetate (100 mL) and washed with H₂O (3×100 mL). The organic layer wasseparated, dried over MgSO₄, filtered, and the solvent was removed undervacuum. The residue was chromatographed over silica gel using (2:1)hexanes/ethyl acetate to afford5′-hydroxymethyl-2,2′:5,2″-diselenophenylfuran.

EXAMPLE 13 Preparation of5′,5″-dihydroxymethyl-2,2′:5,2″-diselenophenylfuran

NaBH₄ (excess) was added to a THF solution (2 mL) containing5′,5″-diformyl-2,2′:5,2″-diselenophenylfuran (15 mg) and stirred at roomtemperature for 5 h. The reaction solution was diluted with ethylacetate (100 mL) and washed with H₂O (3×100 mL). The organic layer wasseparated, dried over MgSO₄, filtered, and the solvent was removed undervacuum. The residue was chromatographed over silica gel using (1:1)hexanes/ethyl acetate to afford5′,5″-dihydroxymethyl-2,2′:5,2″-diselenophenylfuran.

EXAMPLE 14 Preparation of 2,2′:5,2″-diselenophenylthiophene

BCl₃ (1.0 M solution in hexanes, 580 μL) was added dropwise to ananhydrous toluene solution (5 mL) containing2′,2″-diselenophenyl-1,4-diketone (100 mg) andbis(tricyclohexyltin)sulfide (520 mg) under N₂ at room temperature. Thesolution was refluxed for 30 min and cooled to room temperature. Thereaction solution was diluted with ethyl acetate (100 mL) and washedwith H₂O (2×100 mL). The organic layer was separated, dried over MgSO₄,filtered, and the solvent was removed under vacuum. The residue waschromatographed over silica gel using hexanes to afford2,2′:5,2″-diselenophenylthiophene in 85% yield.

EXAMPLE 15 Preparation of 5′-formyl-2,2′:5,2″-diselenophenylthiophene.

LDA (1.0 M solution in THF, 350 μL) was added to an anhydrous THFsolution (4 mL) containing 2,2′:5,2″-diselenophenylthiophene under N₂ at−78° C. The solution was stirred at −78° C. for 3 h, anhydrous DMF (1mL) was added, stirred at −78° C. for 1 h, and slowly warmed to roomtemperature. The reaction solution was diluted with ethyl acetate (50mL) and washed with H₂O (3×100 mL). The organic layer was separated,dried over MgSO₄, filtered, and the solvent was removed under vacuum.The residue was chromatographed over silica gel using CH₂Cl₂ to afford5′-formyl-2,2′:5,2″-diselenophenylthiophene in 80% yield.

EXAMPLE 16 Preparation of5′,5″-diformyl-2,2′:5,2″-diselenophenylthiophene

LDA (1.0 M solution in THF, 1 mL) was added to an anhydrous THF solution(4 mL) containing 2,2′:5,2″-diselenophenylthiophene under N₂ at −78° C.The solution was stirred at −78° C. for 3 h, anhydrous DMF (2 mL) wasadded, the solution was stirred at −78° C. for 1 h, and slowly warmed toroom temperature. The reaction solution was diluted with ethyl acetate(100 mL) and washed with H₂O (3×100 mL). The organic layer wasseparated, dried over MgSO₄, filtered, and the solvent was removed undervacuum. The residue was chromatographed over silica gel using (5:1)CH₂Cl₂/ethyl acetate to afford5′,5″-diformyl-2,2′:5,2″-diselenophenylthiophene in 80% yield.

EXAMPLE 17 Preparation of5′-hydroxymethyl-2,2′:5,2″-diselenophenylthiophene

NaBH₄ (10 mg) was added to a THF solution (3 mL) containing5′-formyl-2,2′:5,2″-diselenophenylthiophene (20 mg) and stirred at roomtemperature for 2 h. The reaction solution was diluted with ethylacetate (50 mL) and washed with H₂O (5×50 mL). The organic layer wasseparated, dried over MgSO₄, filtered, and the solvent was removed undervacuum. The residue was chromatographed over silica gel using (2:1)CH₂Cl₂/ethyl acetate to afford5′-hydroxymethyl-2,2′:5,2″-diselenophenylthiophene in 98% yield.

EXAMPLE 18 Preparation of5,5″-dihydroxymethyl-2,2′:5,2″-diselenophenylthiophene

NaBH₄ (10 mg) was added to a THF solution (3 mL) containing5′,5″-diformyl-2,2′:5,2″-diselenophenylthiophene (20 mg) and stirred atroom temperature for 5 h. The reaction solution was diluted with ethylacetate (50 mL) and washed with H₂O (5×50 mL). The organic layer wasseparated, dried over MgSO₄, filtered, and the solvent was removed undervacuum. The residue was chromatographed over silica gel using (1:1)hexanes/ethyl acetate to afford5′,5″-dihydroxymethyl-2,2′:5,2″-diselenophenylthiophene in 98% yield.

EXAMPLE 19 Preparation of 2,2′:5,2″-diselenophenylpyrrole

An ethanolic solution (20 mL) containing2′,2″-diselenophenyl-1,4-diketone (200 mg) and ammonium acetate (500 mg)and sodium acetate (200 mg) was refluxed overnight. The reactionsolution was diluted with ethyl acetate (100 mL) and washed with H₂O(3×100 mL). The organic layer was separated, dried over MgSO₄, filtered,and the solvent was removed under vacuum. The residue waschromatographed over silica gel using (10:1) hexanes/ethyl acetate toafford 2,2′:5,2″-diselenophenylpyrrole in 94% yield.

EXAMPLE 20 Preparation of 5′-formyl-2,2′:5,2″-diselenophenylpyrrole

LDA (1.0 M solution in THF, 760 μL) was added to an anhydrous THFsolution (5 mL) containing 2,2′:5,2″-diselenophenylpyrrole (100 mg)under N₂ at −78° C. The solution was stirred at −78° C. for 3 h,anhydrous DMF (1.5 mL) was added, the solution was slowly warmed to roomtemperature, and stirred at room temperature for 2 h. The reactionsolution was diluted with ethyl acetate (100 mL) and washed with H₂O(3×100 mL). The organic layer was separated, dried over MgSO₄, filtered,and the solvent was removed under vacuum. The residue waschromatographed over silica gel using (3:1) hexanes/ethyl acetate toafford 5′-formyl-2,2′:5,2″-diselenophenylpyrrole in 75% yield.

EXAMPLE 21 Preparation of5′-hydroxymethyl-2,2′:5,2″-diselenophenylpyrrole

NaBH₄ (20 mg) was added to a THF solution (2 mL) containing5′-formyl-2,2′:5,2″-diselenophenylpyrrole (20 mg) and stirred at roomtemperature for 2 h. The reaction solution was diluted with ethylacetate (50 mL) and washed with H₂O (3×50 mL). The organic layer wasseparated, dried over MgSO₄, filtered, and the solvent was removed undervacuum. The residue was chromatographed over silica gel using (2:1)hexanes/ethyl acetate to afford5′-hydroxymethyl-2,2′:5,2″-diselenophenylpyrrole in 98% yield.

EXAMPLE 22 Preparation of 2′,2″-difuranyl-1,4-diketone

A CH₂Cl₂ solution containing furan (10 mL) and succinyl chloride (2 g)was added dropwise to an anhydrous CH₂Cl₂ solution (100 mL) containingAlCl₃ (10 g) under N₂ at 0° C. The reaction mixture was stirred at 0° C.for 2 h, slowly warmed to room temperature, and stirred for 4 h. Thereaction mixture was poured into a beaker containing ice. Ethyl acetate(300 mL) was added and the organic layer was separated out using aseparatory funnel. The aqueous layer was back washed with ethyl acetate(2×100 mL). The combined organic layer was washed with H₂O (2×300 mL).The organic layer was collected, dried over MgSO₄, filtered, and thesolvent was removed under vacuum. The residue was chromatographed oversilica gel using (3:1) hexanes/ethyl acetate to afford2′,2″-difuranyl-1,4-diketone in 25% yield.

EXAMPLE 23 Preparation of 2,2′:5,2″-difuranylselenophene

BCl₃ (1.0 M solution in hexanes, 900 μL) was added dropwise to ananhydrous toluene solution (00 mL) containing2′,2″-difuranyl-1,4-diketone (100 mg) and bis(tricyclohexyltin)-selenide(750 mg) under N₂ at room temperature. The solution was refluxed for 30min and cooled to room temperature. The reaction solution was dilutedwith ethyl acetate (100 mL) and washed with H₂O (2×100 mL). The organiclayer was separated, dried over MgSO₄, filtered, and the solvent wasremoved under vacuum. The residue was chromatographed over silica gelusing hexanes to afford 2,2′:5,2″-difuranylselenophene in 80% yield.

EXAMPLE 24 Preparation of 5′-formyl-2,2′:5,2″-difuranylselenophene

LDA (1.0 M solution in THF, 420 μL) was added to an anhydrous THFsolution (4 mL) containing 2,2′:5,2″-difuranylselenophene (100 mg) underN₂ at −78° C. The solution was stirred at −78° C. for 3 h, anhydrous DMF(1 mL) was added, the solution was stirred at −78° C. for 1 h, andslowly warmed to room temperature. The reaction solution was dilutedwith ethyl acetate (100 mL) and washed with H₂O (3×100 mL). The organiclayer was separated, dried over MgSO₄, filtered, and the solvent wasremoved under vacuum. The residue was chromatographed over silica gelusing (3:1) hexanes/ethyl acetate to afford5′-formyl-2,2′:5,2″-difuranylselenophene in 75% yield.

EXAMPLE 25 Preparation of 5′,5″-diformyl-2,2′:5,2″-difuranylselenophene

LDA 1.0 M solution in THF, 1 mL) was added to an anhydrous THF solution(4 mL) containing 2,2′:5,2″-difuranylselenophene (100 mg) under N₂ at−78° C. The solution was stirred at −78° C. for 3 h, added anhydrous DMF(2 mL), stirred at −78° C. for 1 h, and slowly warmed to roomtemperature. The reaction solution was diluted with ethyl acetate (100mL.) and washed with H₂O (3×100 mL). The organic layer was separated.dried over MgSQ₄, filtered, and the solvent was removed under vacuum.The residue was chromatographed over silica gel using (2:1)hexanes/ethyl acetate to afford5′,5″-diformyl-2,2′:5,2″-difuranylselenophene in 80% yield.

EXAMPLE 26 Preparation of5′-hydroxymethyl-2,2′:5,2″-difuranylselenophene

NaBH₄ (10 mg) was added to a THF solution (2 mL) containing5′-formyl-2,2′:5,2″-difuranylselenophene (20 mg) and stirred at roomtemperature for 5 h. The reaction solution was diluted with ethylacetate (50 mL) and washed with H₂O (3×50 mL). The organic layer wasseparate(d, dried over MgSO₄, filtered, and the solvent was removedunder vacuum. The residue was chromatographed over silica gel using(2:1) hexanes/ethyl acetate to afford5′-hydroxymethyl-2,2′:5,2″-difuranylselenophene in 98% yield.

EXAMPLE 27 Preparation of5′,5″-dihydroxymethyl-2,2′:5,2″-difuranylselenophene

NaBH₄ (10 mg) was added to a THF solution (2 mL) containing5′,5″-diformyl-2,2′:5,2″-difuranylselenophene (20 mg) and stirred atroom temperature for 5 h. The reaction solution was diluted with ethylacetate (50 mL) and washed with H₂O (3×50 mL). The organic layer wasseparated, dried over MgSO₄, filtered, and the solvent was removed undervacuum. The residue was chromatographed over silica gel using (1:1)hexanes/ethyl acetate to afford5′,5″-dihydroxymethyl-2,2′:5,2″-difuranylselenophene in 98% yield.

EXAMPLE 28 Preparation of 2′,2″-dithienyl-1,4-diketone

A CH₂Cl₂ solution containing thiophene (10 mL) and succinyl chloride (2g) was added dropwise to an anhydrous CH₂Cl₂ solution (100 mL)containing AlCl₃ (10 g) under N₂ at 0° C. The reaction mixture wasstirred at 0° C. for 2 h, slowly warmed to room temperature, and stirredfor 4 h. The reaction mixture was poured into a beaker containing ice.Ethyl acetate (300 mL) was added and the organic layer was separated outusing a separatory funnel. The aqueous layer was back washed with ethylacetate (2×100 mL). The combined organic layer was washed with H₂O(2×300 mL). The organic layer was collected, dried over MgSO₄, and thesolvent was removed under vacuum. The residue was chromatographed oversilica gel using (3:1) hexanes/ethyl acetate to afford2′,2″-dithienyl-1,4-diketone in 25% yield.

EXAMPLE 29 Preparation of 2,2′:5,2″-dithienylselenophene

BCl₃ (1.0 M solution in hexanes, 1.6 mL) was added dropwise to ananhydrous toluene solution (5 mL) containing2′,2″-dithienyl-1,4-diketone (200 mg) and bis(tricyclohexyltin)selenide(1.3 g) under N₂ at room temperature. The solution was refluxed for 30min and cooled to room temperature. The reaction solution was dilutedwith ethyl acetate (100 mL) and washed with H₂O (3×100 mL). The organiclayer was separated, dried over MgSO₄, filtered, and the solvent wasremoved under vacuum. The residue was chromatographed over silica gelusing hexanes to afford 2,2′:5,2″-dithienylselenophene in 90% yield.

EXAMPLE 30 Preparation of 5′-formyl-2,2′:5,2″-dithienylselenophene

LDA (1.0 M solution in THF, 380 μL) was added to an anhydrous THFsolution (4 mL) containing 2,2′:5,2″-dithienylselenophene (100 mg) underN₂ at −78° C. The solution was stirred at −78° C. for 3 h, anhydrous DMF(1 mL) was added, the solution stirred at −78° C. for 1 h, and slowlywarmed to room temperature. The reaction solution was diluted with ethylacetate (100 mL) and washed with H₂O (3×100 mL). The organic layer wasseparated, dried over MgSO₄, filtered, and the solvent was removed undervacuum. The residue was chromatographed over silica gel using (3:1)hexanes/ethyl acetate to afford 5′-formyl-2,2′:5,2″-dithienylselenophenein 75% yield.

EXAMPLE 31 Preparation of 5′,5″-diformyl-2,2′:5,2″-dithienylselenophene

LDA (1.0 M solution in THF, 1.0 mL) was added to an anhydrous THFsolution (4 mL) containing 2,2′:5,2″-dithienylselenophene (100 mg) underN₂ at −78° C. The solution was stirred at −78° C. for 3 h, anhydrous DMF(2 mL) was added, the solution stirred at −78° C. for 1 h, and slowlywarmed to room temperature. The reaction solution was diluted with ethylacetate (100 mL) and washed with H₂O (3×100 mL). The organic layer wasseparated, dried over MgSO₄, filtered, and the solvent was removed undervacuum. The residue was chromatographed over silica gel using (2:1)hexanes/ethyl acetate to afford5′,5″-diformyl-2,2′:5,2″-dithienylselenophene in 85% yield.

EXAMPLE 32 Preparation of5′-hydroxymethyl-2,2′:5,2″-dithienylselenophene

NaBH₄ (10 mg) was added to a THF solution (2 mL) containing5′-formyl-2,2′:5,2″-dithienylselenophene (20 mg) and stirred at roomtemperature for 5 h. The reaction solution was diluted with ethylacetate (50 mL) and washed with H₂O (3×50 mL). The organic layer wasseparated, dried over MgSO₄, filtered, and the solvent was removed undervacuum. The residue was chromatographed over silica gel using (2:1)hexanes/ethyl acetate to afford5′-hydroxymethyl-2,2′:5,2″-dithienylselenophene in 98% yield.

EXAMPLE 33 Preparation of5′,5″-dihydroxymethyl-2,2′:5,2″-dithienylselenophene

NaBH₄ (10 mg) was added to a THF solution (2 mL) containing5′,5″-diformyl-2,2′:5,2″-dithienylselenophene (20 mg) and stirred atroom temperature for 5 h. The reaction solution was diluted with ethylacetate (50 mL) and washed with H₂O (3×50 mL). The organic layer wasseparated, dried over MgSO₄, filtered, and the solvent was removed undervacuum. The residue was chromatographed over silica gel using (1:1)hexanes/ethyl acetate to afford5′,5″-dihydroxymethyl-2,2′:5,2″-dithienylselenophene in 98% yield.

EXAMPLE 34 Alternative Method of Synthesizing Hybrid α-Terselenophenes

In addition to the method of synthesis described in Example 2, analternative synthesis strategy (Scheme 4) can be utilized to preparenumerous “hybrid” α-terselenophenes.

Wherein X, and Y are selected from the group consisting of Se, O, S,N(CH₃)₂ and NH₂, and Z is selected from the group consisting of Se, S,N(CH₃)₂ and NH₂. Various functional groups can be introduced using theapproaches outlined in the synthesis of α-terselenophenes (Scheme 2).

EXAMPLE 35 Preparation of 3-Dimethylamino-1-(2′-selenyl)propanone (1)

Synthesis of 2-acetylselenophene(1): A solution of selenophene (2.0 g,15 mmol), acetic anhydride (2.34 g, 23 mmol) and tin (IV) chloride (0.06g, 23 mmol) in 30 mL of dry methylene chloride was stirred under Argonfor two days until TLC plate showed completion of the reaction.

A mixture of crude 2-acetylselenophene (2.6 g, 15 mmol),paraformaldehyde (0.59 g, 19.6 mmol), dimethylamine hydrochloride (1.6g, 19.5 mmol) and 0.15 mL of HCl was refluxed for 16 h in 7 mL ofethanol. The reaction mixture was cooled and the precipitate wasfiltered, washed with ether and dried; yield 2.77 g (69.3%). ThisMannich base hydrochloride (2 g) was basified using ammonium hydroxide.The solution was extracted (3×15 mL) with diethyl ether. The organiclayer was washed with water and dried with sodium sulfate, and filtered.Evaporation of ether gave 1.6 g of product 2.

¹H NMR (CDCl₃) δ 8.37 (dd, 1H, H-5 of selenophene ring, J=5.52, 0.99),7.95 (dd, 1H, H-3 of selenophene ring, J=0.99, 3.99), 7.40 (dd, 1H, H-4of selenophene ring, J=5.52, 3.99), 3.10 (t, 2H, CO—CH₂, J=7.6), 2.76(t, 2H, CH₂—NMe₂, J=7.6), 2.29 (s, 6H, NMe₂).

EXAMPLE 36 Preparation of 1-(2′-Thienyl)-4-(2″-selenyl)butane-1,4-dione(3)

A solution of 2-formylthiophene (1.05 g, 9.4 mmol) in 4 mL dry DMF wasadded to a suspension of sodium cyanide (0.16 g, 3.4 mmol) in 4 mL, dryDMF After stirring for 10 min, the3-dimethylamino-1-(2′-selenyl)propanone 2 (1.73 g, 7.52 mmol) in 10 mLDMF was added slowly. The mixture was stirred overnight. Water was added(30 mL), and the product was extracted with chloroform (3×30 mL). Theextract was washed with water, dried over sodium sulfate, andevaporated. The product 3 was recrystallized from ethanol; yield: 1.97 g(88.3%). mp: 121-122.40° C. ¹H NMR (500 MHz, CDCl₃) δ 8.37 (dd, 1H, H-5of selenophene ring, J=5.46, 0.91), 8.03 (dd, 1H, H-3 of selenophenering, J=3.92, 0.91), 7.81 (dd, 1H, H-5 of thiophene ring, J=0.94, 3.82),7.63 (dd, 1H, H-3 of thiophene ring, J=4.91, 0.94), 7.40 (dd, 1H, H-4selenophene ring, J=5.46, 0.91), 7.14 (dd, 1H, H-4 of thiophene ring,J=3.82, 4.91), 3.40 (m, 4H, CH₂—CH₂). Anal. Calcd. for C₁₂H₁₀O₂SSe: C,48.49; H, 3.39; S, 10.79. Found: C, 48.83; H, 3.38; S, 10.46.

EXAMPLE 37 Preparation of 2-(2′-Selenyl)-5-(2″-thienyl)thiophene (4)

1-(2′-Thienyl)-4-(2″-selenyl)butane-1,4-dione 3 (1.1 g, 3.70 mmol) andLawesson's reagent (0.99 g, 2.44 mmol) were refluxed overnight in 15 mLtoluene. The toluene was evaporated and the crude product was purifiedusing silica flash column with ether/hexane as eluent. The product 4 wasrecrystallized from methanol; yield: 0.9 g (82.3%). mp. 103-104° C. ¹HNMR (CDCl₃) δ 7.84 (dd, 1H, J=5.57, 1.04), 7.30 (dd, 1H, J=3.78, 1.04),7.20 (m, 2H), 7.15 (dd, 1H, J=3.52, 1.1), 7.00 (m, 3H); ¹³ C NMR (300Mhz, CDCl₃) δ 142.09 (weak), 138.36 (weak), 137.01 (weak), 136.32(weak), 130.29, 129.60, 127.84, 125.73, 124.96, 124.45, 124.29, 123.63.Anal. Calcd. for C₁₂H₈S₂Se: C, 48.81; H, 2.73; S, 21.72. Found: C,49.19; H, 2.58; S, 21.68.

EXAMPLE 38 Preparation of 2-(2′-Selenyl)-5-(2″-thienyl)furene (5)

1-(2′-Thienyl)-4-(2″-selenyl)butane-1,4-dione 3 (0.76 g, 2.56 mmol) wasadded to 35 mL of acetic anhydride, then 3.0 mL of HCl was slowly added.After 4 h at room temperature, the reaction mixture was poured into icewater and extracted with ether. The organic layer was washed with NaHCO₃and water, dried over sodium sulfate, and filtered. After evaporation ofthe solvent, the crude material was subjected to silica columnpurification to give the product 5. Yield: 0.51 g (75.5%). The yellowishwhite solid was recrystallized from methanol. mp. 85-87° C. ¹H NMR(CDCl₃) δ 7.89 (dd, 1H, J=4.51, 1.03), 7.44 (dd, 1H, J=3.82, 1.01), 7.29(dd, 1H, J=3.72, 1.08), 7.26 (dd, 1H, J=4.51, 3.82), 7.22 (dd, 1H,J=5.03, 1.08), 7.03 (dd, 1H, J=5.02, 3.70), 6.53 (m, 2H).

EXAMPLE 39 Preparation of 2-(2′-Selenyl)-5-(2″-thienyl)pyrrole (6)

1-(2′-Thienyl)-4-(2″-selenyl)butane-1,4-dione 3 (0.4 g, 1.35 mmol),sodium acetate (0.33 g, 4.0 mmol) and ammonium acetate (0.78 g, 10.1mmol) were refluxed at 95° C. overnight in 20 mL ethanol. The solventwas evaporated and the crude product 6 was purified using silica flashcolumn with ether/hexane as eluent; yield: 0.27 g (73%). mp. 82-83.5° C.¹H NMR δ 8.26 (br, 1H), 7.81 (d, 1H, J=5.27), 7.25 (dd, 1H, J=3.78,5.27), 7.20 (d, 1H, J=3.78), 7.16 (d, 1H, J=5.01), 7.07 (d, 1H, J=3.60),7.02 (dd, 1H, J=5.01, 3.60), 6.40 (m, 2H).

EXAMPLE 40 Preparation of 1-(2′-Selenyl)-4-(2″-furyl)butane-1,4-dione(7)

A solution of 2-formylfurene (2.27 g, 23.65 mmol) in 20 mL dry DMF wasadded to a suspension of sodium cyanide (0.42 g, 8.45 mmol) in 10 mL dryDMF. After stirring for 10 min, 3-dimethylamino-1-(2′-selenyl)propanone2 (4.3 g, 18.8 mmol) in 20 mL DMF was added slowly. The mixture wasstirred overnight. Water was added (100 mL), and the product wasextracted with chloroform (3×100 mL). The extract was washed with water,dried over sodium sulfate, filtered, and evaporated. The product 7 wasrecrystallized from ethanol; yield: 3.52 g (66.7%). mp. 82-83.5° C. ¹HNMR (CDCl₃) δ 8.35 (dd, 1H, H-5 of selenophene ring, J=5.51, 0.78), 8.01(dd, 1H, H-3 of selenophene ring, J=3.99, 0.79), 7.58 (d, 1H, H-5 offurane ring, J=1.71), 7.39 (dd, 1H, H-4 of selenophene ring, J=5.52,3.99), 7.23 (d, 1H, H-3 of furane ring, J=3.54), 6.53 (dd, 1H, H-4 offurane ring, J=3.54, 1.70), 3.33 (m, 4H, CH₂—CH₂).

EXAMPLE 41 Preparation of 2-(2′-Selenyl)-5-(2″-furyl)thiophene (8)

1-(2′-Selenyl)-4-(2″-furyl)butane-1,4-dione 7 (0.25 g, 0.9 mmol) andLawesson's reagent (0.66 g, 1.63 mmol) were refluxed overnight in 7 mLtoluene. The toluene was evaporated and the crude product was purifiedusing silica flash column. with ether/hexane as eluent. The product 8was recrystallized from methanol; yield: 0.22 g (88%). mp. 76-77° C. ¹HNMR δ 7.86 (dd, 1H, J=5.58, 1.00), 7.40 (d, 1H, J=1.76), 7.31 (dd, 1H,J=3.87, 1.00), 7.23 (dd, 1H, J=5.59, 3.87), 7.11 (d, 1H, J=3.78), 7.03(d, 1H, J=3.81), 6.49 (d, 1H, J=3.36), 6.43 (dd, 1H, J=1.77, 3.36).

EXAMPLE 42 Preparation of 2-(2′-Selenyl)-5-(2″-furyl)pyrrole (9)

1-(2′-Thienyl)-4-(2″-furyl)butane-1,4-dione 7 (0.20 g, 0.71 mmol),sodium acetate (0.18 g, 2.1 mmol) and ammonium acetate (0.41 g, 5.3mmol) were refluxed at 95° C. overnight in 12 mL ethanol. The solventwas evaporated and the crude product 9 was purified using silica flashcolumn with ether/hexane as eluent; yield: 0.15 g (80%). mp. 73-74° C.¹H NMR δ 8.50 (br, 1H), 7.80 (d, 1H, J=5.45), 7.36 (dd, 1H, J=1.02,0.78), 7.22 (m, 2H), 6.40 (in, 4H).

EXAMPLE 43 Preparation of 1,4-Bis-(2′-selenyl)butane-1,4-dione (11)

Synthesis of 2-formylselenophene (10): A solution of selenophene (1.31g, 10 mmol) in 10 mL dichloroethane was added to a mixture of freshlydistilled phosphorus oxychloride (2.0 g, 13 mmol) and DMF (1.10 g, 15mmol). After stirring for 12 h at 60° C., 2 mL water solution of sodiumacetate (2.04 g, 15 mmol) was added to the reaction mixture, and themixture was allowed to react for another hour. Water was added (20 mL),and the product was extracted with dichloromethane (3×20 mL). Theextract was washed with water, dried over sodium sulfate, filtered, andcarefully evaporated.

A solution of crude 2-formylselenophene (454 mg, 2.9 mmol) in 0.6 mL dryDMF was added to a suspension of sodium cyanide (34.3 mg, 0.7 inmol) in0.4 mL dry DMF. After stirring for 5 min, the Mannich base,3-dimethylamino-1-(2-selenyl)-propanone 2 (368 mg, 1.6 mmol) in 1.2 mLDMF was added slowly. The mixture was stirred overnight. Water was added(4 mL, and the product was extracted with dichloromethane (3×6 mL). Theextract was washed with water, dried over sodium sulfate, filtered, andevaporated. The product was purified from silica gel chromatography withTHF/hexane as eluent. Yield: 105 mg (20%). ¹H NMR (CDCl₃) δ 8.37 (dd,1H×2, H-5 of selenophene ring, J=5.53, 1.01), 8.02 (dd, 1H×2, H-3 ofselenophene ring, J=1.00, 3.97), 7.40 (dd, 1H×2, H-4 of selenophenering, J=3.97, 5.50), 3.39 (s, 2H×2, CH₂—CH₂).

EXAMPLE 44 Preparation of 2,5-Bis-(2′-selenyl)-N-methylpyrrol (12)

1,4-Bis-(2′-selenyl)butane-1,4-dione 11 (34.4 mg, 0.1 mmol), sodiumacetate (123 mg, 0.15 mmol) and methylamine chloride (101.3 mg, 0.15mmol) were refluxed overnight in 3 mL ethanol. 10 mL water was thenadded, and the product was extracted with dichloromethane. The product12 was recrystallized from ethanol; yield: 26 mg (76%). ¹H NMR (CDCl₃) δ7.96 (dd, 1H×2, H-5 of selenophene ring J=5.64, 1.64), 7.31 (dd, 1H×2,H-4 of selenophene ring J=5.64, 3.78), 7.20 (dd, 1H×2, H-3 ofselenophene ring J=3.78, 1.64), 6.32 (s, 1H×2, H-¾ of pyrrole ring),3.74 (s, 3H, N—Me).

EXAMPLE 45 Preparation of 2,5-Bis-(2′-thienyl)selenophene (13)

Selenophene (22 mg, 0.28 mmol) and sodium (19.2 mg, 0.83 mmol) werestirred under argon in dry DMF (10 mL at 100° C. until the solutiondecolorized, forming a brown suspension (2 h). The mixture of MeOH andEtOH (1: 1, 2 mL) was added to the suspension at 0° C., followed byaddition of 1,4-bis(2-thienyl)butadiyne (30 mg, 0.139 mmol) in solutionof THF (3 mL). After half hour, the mixture was then poured into water(20 mL) and extracted with ether (3×15 mL). The concentrated organiclayer yielded 28 mg of 13 (68.7%) after silica chromatography. ¹H NMRwas identical with the literature (R. Shabana et al. Phosphorus, Sulfur,and Silicon, 1990, 48, 239-244).

EXAMPLE 46 Preparation of 2,5-Bis-(2′-furyl)selenophene (14)

Selenophene (868 mg 11 mmol) and sodium (757 mg, 33 mmol) were stirredunder argon in dry DMF (15 mL) at 100° C. until the solutiondecolorized, forming a brown suspension (2 h). The mixture of MeOH andEtOH (1: 1, 3 mL) was added to the suspension at 0° C., followed byaddition of 1,4-Bis-(2′-furyl)butadiyne (1 g, 5.5 mmol) in solution ofTHF (3 mL). After half hour, the mixture was poured into water (20 mL)and extracted with ether (3×20 mL). The concentrated organic layeryielded 0.343 g (24%) of 14 after silica chromatography with hexane aseluent. ¹H NMR was identical with the literature (R. Shabana et al.Phosphorus, Sulfur, and Silicon, 1990, 48, 239-244).

EXAMPLE 47 Preparation of 5′-Formyl-2,5-bis-(2′-furyl)selenophene (15)

To a solution of 2,5-bis-(2′-furyl)selenophene 14 (0.12 g, 0.456 mmol)in THF, lithium diisopropyl amide (0.73 mmol) was added at −78° C. underargon. The mixture was stirred below −20° C. for 3 h. A large excess ofDMF (6.5 mmol) was added at −78° C., and the mixture was allowed togradually rise to room temperature. Ether (10 mL) was added, and theorganic solution was washed with water, dried over sodium sulfate,filtered, and evaporated. The crude solid was purified by flash columnchromatography over silica gel (ether/hexane) to give monosubstitutedaldehydes 15. Yield: 78 mg (60%), which was recrystallized fromTHF/hexane to provide pure product. mp: 87.5-89.2° C. ¹H NMR (CDCl₃) δ9.58 (s, 1H), 7.58 (d, 1H, J=4.04), 7.43 (s, 1H), 7.35 (d, 1H, J=4.04),7.26 (d, 1H, J=3.69), 6.64 (d, 1H, J=3.69), 6.57 (d, 1H, J=3.16), 6.46(m, 1H).

EXAMPLE 48 Preparation of 5′-Hydroxymethyl-2,5-bis-(2′-furyl)selenophene(16)

To a solution of 5′-formyl-2,5-bis-(2′-furyl)selenophene (15 mg, 0.05mmol) in 5 mL THF/MeOH (1:1), excess NaBH₄ was added at roomtemperature. The solution was stirred for 2 h. Ethyl acetate was added,and the organic solution was washed with water, dried over sodiumsulfate, and evaporated. The crude solid was purified byrecrystallization from THF/hexane to provide pure product 16. Yield: 14mg (93.4%). mp: 75.0-77.4° C. ¹H NMR (CDCl₃) δ 39 (m, 1H), 7.31 (m, 2H),6.48 (m, 1H), 6.43 (m, 2H), 6.33 (m, 1H). ¹³C NMR (THF-d₈) δ 153.36(weak), 150.99 (weak), 141.81, 136.66 (weak), 136.19 (weak), 125.46(weak), 124.99, 124.71, 111.99, 105.89, 105.15, 57.43.

EXAMPLE 49 Preparation of5′,5″-Diformyl-2-(2′-selenyl)-5-(2″-thienyl)thiophene (17)

To a solution of 2-(2′-selenyl)-5-(2″-thienyl)thiophene 4 (0.45 g, 1.53mmol) in THF was added lithium diisopropyl amide (2.44 mmol) at −78° C.under argon. The mixture was stirred below −20° C. for 3 h. Large excessof DMF (13 mmol) was added at −78° C., and the mixture was allowed togradually rise to room temperature. Ether (30 mL) was added, and theorganic solution was washed with water, dried over sodium sulfate, andevaporated. The crude solid was purified by flash column chromatographyover silica gel (ether/hexane) to give disubstituted aldehydes 17.Yield: 135 mg (27.3%), which was recrystallized from THF/Hexane toprovide pure product. mp: 197.8-199.0° C. ¹H NMR (CDCl₃) δ 9.88 (s, 1H),9.75 (s, 1H), 7.92 (d, III, J=4.28), 7.69 (d, 1H, J=3.87), 7.46 (d, 1H,J=4.28), 7.30 (d, 1H, J=1.93), 7.29 (d, 1H, J=1.93), 7.26 (d, 1H,J=3.87).

EXAMPLE 50 Preparation of5′,5″-Dihydroxymethyl-2-(2′-selenyl)-5-(2″-thienyl)-thiophene (18)

To a solution of 5′,5″-diformyl-2-(2′-selenyl)-5-(2″-thienyl)thiophene(12 mg, 0.03 mmol) in 1.5 mL THF/MeOH (1:1), excessive NaBH₄ was addedat room temperature. The solution was stirred for 4 h. Ethyl acetate wasadded, and the organic solution was washed with water, dried over sodiumsulfate, filtered, and evaporated. The crude solid was purified byrecrystallization from THF/hexane to provide pure product 18. Yield: 8.2mg (68.3%). mp: 187.1-188.8° C. ¹H NMR (CDCl₃) δ 7.20 (d, 1H, J=3.76),7.07 (m, 3H), 7.00 (d, 1H, J=3.66), 6.88 (d, 1H, J=3.39), 5.56 (t, 1H,OH), 5.45 (t, 1H, OH), 4.65 (m, 4H, 2CH₂).

EXAMPLE 51 Synthesis of Water Soluble Analogs

A highly polar functional group can be incorporated into the selenophenecompounds in order to improve their water solubility. Addition of acarbonylic functional group through an ester linkage (Scheme 5) resultedin a transient solubility. However, the benzylic ester may be readilyhydrolyzed to regenerate the water insoluble starting material.

On the basis of the synthesis for hybrid α-terselenophenes (Scheme 3), anitrogen atom can be introduced into the five-membered ring system(Scheme 6). Conversion of the hydroxyl group of the intermediatecompound of Scheme 3 into an amino group can improve water solubility.Further modification of its formulation may further enhance solubilityto >1 mg/mL H₂O. The ammonium analog should be highly water soluble.

To maximize the efficiency of synthesizing hybrid α-terselenophenes,Scheme 1 can be modified to produce related selenophene analogs inaccordance with Scheme 7:

EXAMPLE 52 Synthesis of Prodrugs

An alternative approach of enhancing the water solubility of hydrophobicdrugs comprises the preparation of their polar prodrug analogs.

a. Glycosides: Preliminary results indicate that β-D-glucoside of2-hydroxymethyl-α-terthiophene retains both its in vitro and in vivoactivities. Scheme 8 illustrates a procedure utilized for the synthesisof glucoside, galactoside or, glucuronic acid analogs ofα-terselenophene:

b. Glutamate Conjugate: As mentioned above, conversion of the hydroxylgroup of 2-hydroxymnethyl-5,2′:5′,2″-terselenophene into its aminoanalog can moderately improve its water solubility. However, the aminoanalog is less stable. The amino analog may be trans formed into itsγ-glutamate prodrug (as shown in Scheme 9) to further enhance its watersolubility and stability. This conjugate may also enhance targetselectivity for the treatment of kidney cancer because of the higherγ-glutamyl transpeptidase activity in kidney. A modified procedure canalso be designed for the preparation of glutathione conjugate.

c. Formation of Inclusion Complexes

The hydrophobic cavity of cyclodextrin derivatives can form stableinclusion complexes with 2-aminomethyl substituted thiophene compounds.β-Cyclodextrin (cyclic heptaamylose) derivatives are commonly used forimproving water solubility because of their low costs. It is anticipatedthat the selenophene compounds of the present invention can be complexedwith β-hydroxypropyl, dimethyl and sulfated β-cyclodextrins to enhancethe water solubility of those compounds.

EXAMPLE 53

Additional National Cancer Institute data demonstrating selenophenegrowth inhibition of human cancer cell lines is represented in thefollowing tables. The compound must exhibit a Log₁₀ GI₅₀ value of <−4.00to be considered active against the tested cell line. NSC: 688829

Panel/Cell Line Log₁₀ GI₅₀ Log₁₀ TGI Log₁₀ LC₅₀ Leukemia CCRF-CEM−5.10 >−4.00 >−4.00 K-562 −6.60 >−4.00 >−4.00 MOLT-4 −4.24 >−4.00 >−4.00RPMI-8226 −4.41 >−4.00 >−4.00 SR −4.61 −4.14 >−4.00 Non-Small Cell LungCancer A549/ATCC >−4.00 >−4.00 >−4.00 EKVX −6.60 >−4.00 >−4.00 HOP-62−4.01 −4.80 >−4.00 HOP-92 −6.05 >−4.00 >−4.00NCI-H226 >−4.00 >−4.00 >−4.00 NCI-H23 −4.56 >−4.00 >−4.00 NCI-H322M−6.85 −4.05 >−4.00 NCI-H460 −4.95 >−4.00 >−4.00 NCI-H522 −4.40 >−4.00Colon Cancer COLO 205 −4.92 −4.48 −4.04 HCC-2998 −6.41 >−4.00 >−4.00HCT-116 −6.53 >−4.00 >−4.00 HCT-15 −4.64 >−4.00 >−4.00 HT29−4.63 >−4.00 >−4.00 KM12 >−4.00 >−4.00 SW-620 −6.08 >−4.00 >−4.00 CNSCancer SF-295 >−4.00 >−4.00 >−4.00 SF-539 −4.56 >−4.00 >−4.00SNB-19 >−4.00 >−4.00 >−4.00 SNB-75 −4.12 >−4.00 >−4.00 U251 −6.61−4.59 >−4.00 Melanoma LOX IMVI −4.78 >−4.00 >−4.00 MALME-3M−4.54 >−4.00 >−4.00 M14 −4.70 >−4.00 >−4.00 SK-MEL-2 −4.47 >−4.00 >−4.00SK-MEL-28 −4.18 >−4.00 >−4.00 SK-MEL-5 −4.63 >−4.00 >−4.00 UACC-257−6.71 −6.29 >−4.00 UACC-62 −6.85 >−4.00 >−4.00 Ovarian Cancer IRGOV1−6.75 −5.61 −4.04 OVCAR-3 −6.89 −6.20 >−4.00 OVCAR-4 −6.73 >−4.00OVCAR-5 −6.91 −6.30 >−4.00 OVCAR-8 −4.82 −4.03 >−4.00 SK-OV-3−4.58 >−4.00 >−4.00 Renal Cancer 786-0 −4.57 −4.19 A498 −7.67 −7.10−6.48 ACHN >−4.00 >−4.00 >−4.00 CAKI-1 −6.72 −6.30 −4.53 SN12C −4.55−4.07 >−4.00 TK-10 −7.55 −6.68 −4.21 UO-31 >−4.00 >−4.00 >−4.00 ProstateCancer PC-3 −4.55 >−4.00 >−4.00 DU-145 >−4.00 >−4.00 >−4.00 BreastCancer MCF7 −6.72 >−4.00 >−4.00 MCF7/ADR-RES −4.52 >−4.00 >−4.00MDA-MB-231/ATCC −4.63 −4.17 >−4.00 HS 578T −5.54 >−4.00 >−4.00MDA-MB-435 −4.48 >−4.00 >−4.00 MDA-N −4.68 >−4.00 >−4.00 BT-549−4.25 >−4.00 >−4.00 T-47D −6.47 >−4.00 >−4.00 MG_MID −5.27 −4.35 −4.06Delta 2.40 2.75 2.42 Range 3.67 3.10 2.48

NSC: 688830

Panel/Cell Line Log₁₀ GI₅₀ Log₁₀ TGI Log₁₀ LC₅₀ Leukemia CCRF-CEM−4.59 >−4.00 >−4.00 K-562 −7.14 −4.76 −4.01 MOLT-4 −4.41 >−4.00 >−4.00RPMI-8226 −4.43 >−4.00 >−4.00 SR −4.61 −4.14 >−4.00 Non-Small Cell LungCancer A549/ATCC −5.22 −4.48 >−4.00 EKVX −4.71 −4.18 >−4.00 HOP-62 −7.21−4.55 −4.07 HOP-92 −4.55 >−4.00 >−4.00 NCI-H322M −7.22 >−4.00 NCI-H23−4.07 >−4.00 >−4.00 NCI-H322M −5.47 −4.70 >−4.00 NCI-H460 −7.77 −6.19−4.54 NCI-H522 >−4.00 >−4.00 >−4.00 Colon Cancer COLO 205 −6.35 −5.26−4.21 HCC-2998 −7.20 −4.94 −4.35 HCT-116 −7.56 −4.76 −4.09 HCT-15−4.54 >−4.00 >−4.00 HT29 −6.65 −4.36 >−4.00 KM12 −4.32 >−4.00 >−4.00SW-620 −7.40 −4.60 >−4.00 CNS Cancer SF-295 −4.68 −4.25 >−4.00 SF-539−4.81 −4.44 −4.08 SNB-19 −4.47 −4.06 >−4.00 SNB-75 −4.59 >−4.00 >−4.00U251 −7.08 −4.68 −4.14 Melanoma LOXIMVI −4.87 −4.56 −4.25 MALME-3M−4.36 >−4.00 >−4.00 M14 −4.43 >−4.00 >−4.00 SK-MEL-2 −4.40 >−4.00 >−4.00SK-MEL-28 >−4.00 >−4.00 >−4.00 SK-MEL-5 −4.44 >−4.00 >−4.00 UACC-7257−7.78 −7.34 −6.62 UACC-62 −7.87 >−4.00 >−4.00 Ovarian Cancer IRGOV1−7.85 −6.76 −4.55 OVCAR-3 <−8.00 −7.25 −4.30 OVCAR-4 −6.98 −4.09 OVCAR-5−7.64 >−4.00 OVCAR-8 −5.16 −4.51 >−4.00 SK-OV-3 −5.49 −4.71 −4.29 RenalCancer 786-0 −5.19 −4.64 −4.24 A498 <−8.00 −7.61 −7.14 ACHN−4.68 >−4.00 >−4.00 CAKI-1 <−8.00 −7.55 SN12C −4.31 >−4.00 >−4.00 TK-10<−8.00 −7.43 −4.19 UO-31 >−4.00 >−4.00 >−4.00 Prostate Cancer PC-3−4.51 >−4.00 >−4.00 DU-145 −4.64 >−4.00 >−4.00 Breast Cancer MCF7−7.78 >−4.00 >−4.00 MCF7/ADR-RES −4.91 >−4.00 >−4.00 MDA-MB-231/ATCC−4.90 −4.45 −4.01 HS 578T >−4.00 >−4.00 MDA-N −4.01 >−4.00 >−4.00BT-549 >−4.00 >−4.00 >−4.00 T-47D −6.54 −4.24 MG_MID −5.64 −4.62 −4.16Delta 2.36 2.99 2.98 Range 4.00 3.61 3.14

NSC: 676631

Panel/Cell Line Log₁₀ GI₅₀ Log₁₀ TGI Log₁₀ LC₅₀ LeukemiaCCRF-CEM >−4.00 >−4.00 >−4.00 HL-60(TB) >−4.00 >−4.00 >−4.00 K-562−6.99 >−4.00 >−4.00 MOLT-4 >−4.00 >−4.00 >−4.00RPMI-8226 >−4.00 >−4.00 >−4.00 SR >−4.00 >−4.00 >−4.00 Non-Small CellLung Cancer A549/ATCC −4.23 >−4.00 >−4.00 EKVX >−4.00 >−4.00 >−4.00HOP-62 >−4.00 >−4.00 HOP-92 >−4.00 >−4.00 >−4.00 NCI-H226 −7.30 −6.74−6.28 NCI-H23 −4.78 −4.41 −4.04 NCI-H322M −4.66 >−4.00 >−4.00NCI-H460 >−4.00 >−4.00 NCI-H522 −5.28 −4.67 −4.26 Colon Cancer COLO 205−6.54 −4.90 −4.18 HCC-2998 −4.37 >−4.00 >−4.00 HCT-116−7.27 >−4.00 >−4.00 HCT-15 −4.56 >−4.00 >−4.00 HT29 >−4.00 >−4.00 KM12−4.57 >−4.00 >−4.00 SW-620 −6.45 >−4.00 >−4.00 CNS Cancer SF-268 −4.63−4.19 >−4.00 SF-295 −4.26 >−4.00 >−4.00 SF-539 −4.91 −4.24 >−4.00 SNB-19−4.76 >−4.00 >−4.00 SNB-75 −4.38 >−4.00 >−4.00 U251 −7.11 −4.70 −4.35Melanoma LOX IMVI −4.82 −4.44 −4.07 MALME-3M >−4.00 >−4.00 >−4.00 M14−4.70 >−4.00 >−4.00 SK-MEL-2 >−4.00 >−4.00 >−4.00 SK-MEL-28−4.18 >−4.00 >−4.00 SK-MEL-5 >−4.00 >−4.00 >−4.00 UACC-257 −7.50 >−4.00−6.34 UACC-62 −7.58 −6.94 >−4.00 Ovarian Cancer IRGOV1 −7.09 −6.22 −4.29OVCAR-3 −7.56 −6.86 −4.39 OVCAR-4 >−4.00 >−4.00 OVCAR-5 −7.50 −6.68OVCAR-8 −4.61 >−4.00 >−4.00 SK-OV-3 −4.34 >−4.00 >−4.00 Renal Cancer786-0 >−4.00 >−4.00 >−4.00 A498 −7.56 −7.08 −6.52ACHN >−4.00 >−4.00 >−4.00 CAKI-1 −7.52 −6.72 −4.19 RXF-393−4.14 >−4.00 >−4.00 SN12C >−4.00 >−4.00 >−4.00 TK-10 −7.30 −6.43 −4.14UO-31 >−4.00 >−4.00 >−4.00 Prostate Cancer PC-3 −4.28 >−4.00 >−4.00DU-145 −4.70 −4.11 >−4.00 Breast Cancer MCF7 −7.03 −4.66 >−4.00MCF7/ADR-RES −5.00 −4.50 −4.01 MDA-MB-231/ATCC −4.72 −4.06 >−4.00 HS578T >−4.00 >−4.00 >−4.00 MDA-MB-435 −5.09 −4.26 >−4.00 MDA-N −4.78−4.36 >−4.00 BT-549 −4.77 −4.42 −4.06 T-47D −6.17 >−4.00 >−4.00 MG_MID−5.18 −4.47 −4.15 Delta 2.40 2.61 2.37 Range 3.58 3.08 2.52

NSC: 675246

Panel/Cell Line Log₁₀ GI₅₀ Log₁₀ TGI Log₁₀ LC₅₀ Leukemia CCRF-CEM −5.50−4.91 >−4.00 HL-60(TB) −5.24 >−4.00 >−4.00 K-562 −6.43 −5.12 >−4.00MOLT-4 −5.49 −4.92 >−4.00 RPMI-8226 −5.13 >−4.00 >−4.00 SR−5.18 >−4.00 >−4.00 Non-Small Cell Lung Cancer A549/ATCC −4.98 −4.65−4.33 EKVX −5.26 −4.76 −4.37 HOP-62 −5.14 −4.69 −4.35 HOP-92 −5.58 −4.95−4.42 NCI-H322M −6.21 −5.63 NCI-H23 −4.88 −4.51 −4.15 NCI-H322M −4.97−4.65 −4.32 NCI-H460 −6.49 −5.44 −4.64 NCI-H52 −5.61 −5.18 −4.63 ColonCancer COLO 205 −6.00 −5.39 >−4.00 HCC-2998 −5.91 −4.93 −4.27 HCT-116−7.19 −4.97 −4.49 HCT-15 −5.37 −4.75 >−4.00 HT29 −6.07 −4.97 −4.23 KM12−5.38 −4.77 −4.28 SW-620 −6.38 −4.99 −4.45 CNS Cancer SF-268−5.39 >−4.00 >−4.00 SF-295 −4.97 −4.56 −4.14 SF-539 −4.91 −4.60 −4.29SNB-19 −4.91 −4.28 >−4.00 SNB-75 −5.41 >−4.00 >−4.00 U251 −7.15 −4.91−4.26 Melanoma LOXIMVI −5.44 −5.01 −4.43 MALME-3M −5.21 −4.71 −4.30 M14−5.06 −4.62 −4.21 SK-MEL-2 −5.04 −4.59 −4.16 SK-MEL-28 −5.13 −4.66 −4.27SK-MEL-5 −5.58 −5.05 −4.53 UACC-257 −7.30 −6.65 UACC-62 −7.99 −4.95−4.17 Ovarian Cancer IRGOV1 −7.27 −5.65 −4.91 OVCAR-3 −7.22 −5.89 −5.16OVCAR-4 −6.24 −4.91 −4.32 OVCAR-5 −6.74 −4.60 >−4.00 OVCAR-8 −5.30−4.48 >−4.00 Renal Cancer 786-0 −5.66 −5.28 −4.76 A498 −7.41 −6.78 −6.16CAKI-1 −5.27 −4.73 −4.29 RXF-303 −7.68 −7.04 TK-10 −5.72 −4.97 >−4.00UO-31 −5.21 −4.41 >−4.00 −7.50 −6.65 −4.05 −4.92 −4.61 −4.29 ProstateCancer PC-3 −5.42 −4.88 −4.44 DU-145 −4.99 −4.66 −4.33 Breast CancerMCF7 −6.84 −5.42 −4.53 MCF7/ADR-RES −5.29 −4.33 >−4.00 MDA-MB-231/ATCC−5.36 −4.47 >−4.00 MDA-N −5.01 −4.25 >−4.00 T-47D −5.42 −4.82 −4.35−5.56 −4.90 −4.40 −5.20 −4.68 −4.26 −5.63 −4.33 >−4.00 MG_MID −5.78−4.91 −4.29 Delta 2.22 2.14 1.88 Range 3.11 3.04 2.16

NSC: 675247

Panel/Cell Line Log₁₀ GI₅₀ Log₁₀ TGI Log₁₀ LC₅₀ Leukemia CCRF-CEM −5.47−5.00 >−4.00 HL-60(TB) −5.39 K-562 −5.88 −5.30 −4.15 MOLT-4 −5.48−5.08 >−4.00 RPMI-8226 −5.39 >−4.00 >−4.00 SR −5.43 >−4.00 >−4.00 >−4.00Non-Small Cell Lung Cancer A549/ATCC −5.34 −4.71 −4.27 EKVX −5.30−4.46 >−4.00 HOP-62 −5.26 −4.67 −4.24 HOP-92 −5.62 −5.12 −4.26 NCI-H226−5.77 −5.41 −5.04 NCI-H23 −5.18 −4.60 −4.02 NCI-H322M −4.95 −4.61 −4.28NCI-H460 −6.28 −5.00 −4.09 NCI-H522 −5.78 −5.47 −5.15 Colon Cancer COLO205 −5.71 −5.29 −4.75 HCC-2998 −6.07 −5.49 −4.90 HCT-116 −6.27−4.95 >−4.00 HCT-15 −5.42 −4.91 −4.26 HT29 −5.79 −5.12 −4.18 KM12 −5.35−4.82 −4.30 SW-620 −5.87 −5.44 −5.02 CNS Cancer SF-268 −5.76 −5.36 −4.68SF-295 −4.93 −4.54 −4.15 SF-539 −4.76 −4.39 −4.02 SNB-19 −5.26 −4.60−4.04 SNB-75 −4.83 −4.41 >−4.00 U251 −6.33 −4.91 −4.30 Melanoma LOX IMVI−5.52 −5.51 >−4.00 MALME-3M −5.54 −4.97 −4.25 M14 −5.43 −4.89 −4.31SK-MEL-2 −5.15 −4.62 −4.16 SK-MEL-28 −5.29 >−4.00 >−4.00 SK-MEL-5 −5.84−5.52 −5.20 UACC-257 −6.36 −5.70 −4.50 UACC-62 −6.81 −5.61 −4.35 OvarianCancer IRGOV1 −5.86 −5.19 −4.52 OVCAR-3 −6.68 −5.93 −5.27 OVCAR-4 −5.77−5.16 −4.31 OVCAR-5 −5.88 −4.89 >−4.00 OVCAR-8 −5.43 −4.75 −4.14 RenalCancer 786-0 −5.56 −5.20 −4.15 A498 −6.42 −5.85 −5.14 ACHN−5.40 >−4.00 >−4.00 CAKI-1 −7.13 −6.33 −4.88 RXF-393 −5.80 −5.43 −5.06SN12C −5.56 −4.93 >−4.00 TK-10 −6.86 −6.18 −4.80 UO-31 −5.28 −4.83 −4.41Prostate Cancer PC-3 −5.45 −4.91 −4.45 DU-145 −5.16 −4.71 −4.33 BreastCancer MCF7 −6.80 −4.95 −4.32 MCF7/ADR-RES −5.42 −4.58 >−4.00MDA-MB-3221/ATCC −5.30 −4.79 −4.32 HS 578T −5.27 −4.44 >−4.00 MDA-MB-435−5.49 −4.95 −4.33 MDA-N −5.52 −5.01 −4.31 BT-549 −5.11 −4.60 −4.13 T-47D−5.47 −4.85 >−4.00 MG_MID −5.65 −4.98 −4.34 Delta 1.48 1.36 0.93 Range2.37 2.33 1.27

NSC: 675343

Panel/Cell Line Log₁₀ GI₅₀ Log₁₀ TGI Log₁₀ LC₅₀ Leukemia CCRF-CEM −4.65−4.22 >−4.00 HL-60(TB) −4.21 >−4.00 >−4.00 K-562 <−8.00 −4.58 >−4.00MOLT-4 −4.54 −4.06 >−4.00 RPMI-8226 >−4.00 >−4.00 >−4.00SR >−4.00 >−4.00 >−4.00 Non-Small Cell Lung CancerA549/ATCC >−4.00 >−4.00 >−4.00 EKVX >−4.00 >−4.00 >−4.00HOP-62 >−4.00 >−4.00 >−4.00 HOP-92 −4.39 >−4.00 >−4.00 NCI-H226 <−8.00−7.14 >−4.00 NCI-H23 >−4.00 >−4.00 >−4.00 NCI-H322M −5.01 >−4.00 >−4.00NCI-H460 <−8.00 >−4.00 >−4.00 NCI-H522 −4.00 >−4.00 >−4.00 Colon CancerCOLO 205 <−8.00 −5.98 −4.64 HCC-2998 <−8.00 −5.47 >−4.00 HCT-116<−8.00 >−4.00 >−4.00 HCT-15 >−4.00 >−4.00 >−4.00 HT29 >−4.00 >−4.00KM12 >−4.00 >−4.00 >−4.00 SW-620 <−8.00 >−4.00 >−4.00 CNS CancerSF-268 >−4.00 >−4.00 >−4.00 SF-295 >−4.00 >−4.00 >−4.00SF-539 >−4.00 >−4.00 >−4.00 SNB-19 >−4.00 >−4.00 >−4.00 SNB-75 U251<−8.00 >−4.00 >−4.00 Melanoma LOX IMVI >−4.00 >−4.00 >−4.00MALME-3M >−4.00 >−4.00 >−4.00 M14 >−4.00 >−4.00 >−4.00SK-MEL-2 >−4.00 >−4.00 >−4.00 SK-MEL-28 >−4.00 >−4.00 >−4.00SK-MEL-5 >−4.00 >−4.00 UACC-257 <−8.00 <−8.00 UACC-62<−8.00 >−4.00 >−4.00 Ovarian Cancer OVCAR-3 −7.59 −4.49 >−4.00 OVCAR-4<−8.00 >−4.00 >−4.00 OVCAR-5 −6.80 >−4.00 >−4.00 OVCAR-8<−8.00 >−4.00 >−4.00 SK-OV-3 >−4.00 >−4.00 >−4.00 Renal Cancer786-0 >−4.00 >−4.00 >−4.00 A498 <−8.00 <−8.00 −6.80ACHN >−4.00 >−4.00 >−4.00 CAKI-1 <−8.00 <−8.00 >−4.00 RXF-393−4.68 >−4.00 >−4.00 SN12C >−4.00 >−4.00 >−4.00 TK-10 <−8.00<−8.00 >−4.00 UO-31 >−4.00 >−4.00 >−4.00 Prostate CancerPC-3 >−4.00 >−4.00 >−4.00 DU-145 >−4.00 >−4.00 >−4.00 Breast Cancer MCF7<−8.00 >−4.00 >−4.00 MCF7/ADR-RES >−4.00 >−4.00 >−4.00MDA-MB-2312/ATCC >−4.00 >−4.00 >−4.00 HS 578T >−4.00 >−4.00 >−4.00MDA-MB-435 >−4.00 >−4.00 >−4.00 MDA-N >−4.00 >−4.00 >−4.00BT-549 >−4.00 >−4.00 >−4.00 T-47D −6.14 >−4.00 >−4.00 MG_MID −5.36 −4.41−4.06 Delta 2.64 3.59 2.74 Rannge 4.00 4.00 2.80

NSC: 676632

Panel/Cell Line Log₁₀ GI₅₀ Log₁₀ TGI Log₁₀ LC₅₀ Leukemia CCRF-CEM−4.06 >−4.00 >−4.00 HL-60(TB) >−4.00 >−4.00 >−4.00 K-562−7.32 >−4.00 >−4.00 MOLT-4 >−4.00 >−4.00 >−4.00RPMI-8226 >−4.00 >−4.00 >−4.00 SR >−4.00 >−4.00 >−4.00 Non-Small CellLung Cancer A549/ATCC −5.58 >−4.00 >−4.00 EKVX −4.30 >−4.00 >−4.00HOP-62 −7.12 >−4.00 >−4.00 HOP-92 >−4.00 >−4.00 >−4.00 NCI-H226 −7.71−7.27 −6.49 NCI-H23 >−4.00 >−4.00 >−4.00 NCI-H322M >−4.00 >−4.00 >−4.00NCI-H460 −7.33 >−4.00 >−4.00 NCI-H522 >−4.00 >−4.00 >−4.00 Colon CancerHCC-2998 −6.75 −6.26 −5.61 HCT-116 >−4.00 >−4.00 >−4.00 HCT-15−7.35 >−4.00 >−4.00 HT29 >−4.00 >−4.00 >−4.00 KM12 −6.27 >−4.00 >−4.00SW-620 >−4.00 >−4.00 >−4.00 −6.82 >−4.00 >−4.00 CNS CancerSF-268 >−4.00 >−4.00 >−4.00 SF-295 >−4.00 >−4.00 >−4.00SF-539 >−4.00 >−4.00 >−4.00 SNB-19 −4.37 >−4.00 >−4.00SNB-75 >−4.00 >−4.00 >−4.00 U251 −7.45 −4.92 −4.33 Melanoma LOXIMVI >−4.00 <−4.00 >−4.00 MALME-3M >−4.00 >−4.00 >−4.00M14 >−4.00 >−4.00 >−4.00 SK-MEL-2 >−4.00 >−4.00 >−4.00SK-MEL-28 >−4.00 >−4.00 >−4.00 SK-MEL-5 −4.20 >−4.00 >−4.00 UACC-257−7.67 >−4.00 UACC-62 −7.65 −7.25 >−4.00 Ovarian Cancer IRGOV1 −7.49−6.56 >−4.00 OVCAR-3 −7.71 −7.17 >−4.00 OVCAR-4 −6.87 >−4.00 OVCAR-5−7.88 −7.11 −6.11 OVCAR-8 >−4.00 >−4.00 >−4.00 >−4.00 >−4.00 >−4.00Renal Cancer 786-0 >−4.00 >−4.00 >−4.00 A498 −7.73 −7.37 −7.02ACHN >−4.00 >−4.00 >−4.00 CAKI-1 −7.90 −6.91 >−4.00RXF-393 >−4.00 >−4.00 >−4.00 SN12C >−4.00 >−4.00 >−4.00 TK-10 −7.55−7.09 >−4.00 UO-31 >−4.00 >−4.00 >−4.00 Prostate CancerPC-3 >−4.00 >−4.00 >−4.00 DU-145 −4.02 >−4.00 >−4.00 Breast Cancer MCF7−7.91 >−4.00 >−4.00 MCF7/ADR-RES >−4.00 >−4.00 >−4.00MDA-MB-231/ATCC >−4.00 >−4.00 >−4.00 HS578T >−4.00 >−4.00 >−4.00MDA-MB-435 >−4.00 >−4.00 >−4.00 MDA-N >−4.00 >−4.00 >−4.00BT-549 >−4.00 >−4.00 >−4.00 T-47D −6.71 >−4.00 >−4.00 MG_MID −5.16 −4.48−4.16 Delta 2.75 2.89 2.86 Range 3.91 3.37 3.02

NSC: 675344

Panel/Cell Line Log₁₀ GI₅₀ Log₁₀ TGI Log₁₀ LC₅₀ LeukemiaCCRF-CEM >−4.00 >−4.00 >−4.00 HL-60(TB) >−4.00 >−4.00 >−4.00 K-562−7.36 >−4.00 >−4.00 MOLT-4 >−4.00 >−4.00 >−4.00RPMI-8826 >−4.00 >−4.00 >−4.00 SR >−4.00 >−4.00 >−4.00 Non-Small CellLung Cancer A549/ATCC −4.34 >−4.00 >−4.00 EKVX >−4.00 >−4.00 >−4.00HOP-62 −4.46 >−4.00 >−4.00 HOP-92 −4.56 −4.05 >−4.00 NCI-H226 <−8.00<−8.00 −6.65 NCI-H23 −4.69 >−4.00 >−4.00 NCI-H322M −4.68 >−4.00 >−4.00NCI-H460 <−8.00 >−4.00 >−4.00 NCI-H522 >−4.00 >−4.00 >−4.00 Colon CancerHCC-2998 −6.59 −5.79 −5.01 HCT-116 <−8.00 −7.38 −5.53 HCT-15−7.59 >4.00 >−4.00 HT29 >4.00 >−4.00 >−4.00 KM12 >−4.00 >−4.00 >−4.00SW-620 >4.00 >−4.00 >−4.00 −7.06 >−4.00 >−4.00 CNS Cancer SF-268−4.63 >−4.00 >−4.00 SF-295 −4.57 >−4.00 >−4.00SF-539 >−4.00 >−4.00 >−4.00 SNB-19 −4.53 >−4.00 >−4.00 SNB-75 −4.78−4.31 >−4.00 U251 −7.60 −4.58 >−4.00 Melanoma LOX IMVI−4.46 >−4.00 >−4.00 MALME-3M >−4.00 >−4.00 >−4.00M14 >−4.00 >−4.00 >−4.00 SK-MEL-2 >−4.00 >−4.00 >−4.00SK-MEL-28 >−4.00 >−4.00 >−4.00 SK-MEL-5 >−4.00 >−4.00 >−4.00 UACC-257<−8.00 −7.73 −7.28 UACC-62 <−8.00 −7.85 >−4.00 Ovarian Cancer IGROV1−7.91 −7.37 −4.79 OVCAR-3 <−8.00 >−4.00 >−4.00 OVCAR-4−7.38 >−4.00 >−4.00 OVCAR-5 <−8.00 −7.06 >−4.00OVCAR-8 >−4.00 >−4.00 >−4.00 SK-OV-3 −4.78 >−4.00 >−4.00 Renal Cancer786-0 −4.91 −4.17 >−4.00 A498 <−8.00 −7.74 −7.18 ACHN −4.89 −4.08 >−4.00RXF-393 −4.80 −4.28 >−4.00 SN12C >−4.00 >−4.00 >−4.00 TK-10 <−8.00−7.30 >−4.00 UO-31 >−4.00 >−4.00 >−4.00 Prostate CancerPC-3 >−4.00 >−4.00 >−4.00 DU-145 −4.44 >−4.00 >−4.00 Breast Cancer MCF7−6.90 >−4.00 >−4.00 MCF7/ADR-RES >−4.00 >−4.00 >−4.00 MDA-MB-231/ATCC−4.72 >−4.00 >−4.00 MS 578T −4.27 >−4.00 >−4.00MDA-MB-435 >−4.00 >−4.00 >−4.00 MDA-N >−4.00 >−4.00 >−4.00 BT-549−4.37 >−4.00 >−4.00 T-47D −6.21 >−4.00 >−4.00 MG_MID −5.28 −4.54 −4.21Delta 2.72 3.46 3.07 Range 4.00 4.00 3.28

NSC: 676630

Panel/Cell Line Log₁₀ GI₅₀ Log₁₀ TGI Log₁₀ LC₅₀ LeukemiaCCRF-CEM >−4.00 >−4.00 >−4.00 HL-60(TB) >−4.00 >−4.00 >−4.00 K-562−5.47 >−4.00 >−4.00 MOLT-4 >−4.00 >−4.00 >−4.00RPMI-8226 >−4.00 >−4.00 >−4.00 SR >−4.00 >−4.00 >−4.00 Non-Small CellLung Cancer A549/ATCC −4.06 >−4.00 >−4.00 EKVX >−4.00 >−4.00 >−4.00HOP-62 >−4.00 >−4.00 HOP-92 >4.00 >−4.00 >−4.00 NCI-H226 −6.72 −6.31−5.61 NCI-H23 >−4.00 >−4.00 NCI-H322M >−4.00 >−4.00 >−4.00 NCI-H460−6.89 >−4.00 >−4.00 NCI-H522 −4.68 −4.27 >−4.00 Colon Cancer COLO 205−4.03 >−4.00 >−4.00 NCC-2998 −4.07 >−4.00 HCT-116 −5.52 >−4.00 >−4.00NCT-15 >−4.00 >−4.00 >−4.00 HT29 >−4.00 >−4.00 >−4.00KM12 >−4.00 >−4.00 >−4.00 SW-620 >−4.00 >−4.00 >−4.00 CNS CancerSF-268 >−4.00 >−4.00 >−4.00 SF-295 >−4.00 >−4.00 >−4.00SF-539 >−4.00 >−4.00 >−4.00 SNB-19 >−4.00 >−4.00 >−4.00 SNB-75−4.17 >−4.00 >−4.00 U251 −6.23 >−4.00 >−4.00 Melanoma LOCIMVI >−4.00 >−4.00 >−4.00 MALME-3M >−4.00 >−4.00 >−4.00M14 >−4.00 >−4.00 >−4.00 SK-MEL-2 >−4.00 >−4.00 >−4.00SK-MEL-28 >−4.00 >−4.00 >−4.00 SK-MEL-5 >−4.00 >−4.00 >−4.00 UACC-257−6.56 −6.17 −5.16 UACC-62 −6.58 >−4.00 >−4.00 Ovarian Cancer IRGOV1−5.83 >−4.00 >−4.00 OVCAR-3 −6.14 >−4.00 >−4.00 OVCAR-4 >−4.00 OVCAR-5−6.88 −6.35 −5.45 OVCAR-8 −4.48 >−4.00 >−4.00SK-OV-3 >−4.00 >−4.00 >−4.00 Renal Cancer 786-0 >−4.00 >−4.00 >−4.00ACHN >−4.00 >−4.00 >−4.00 CAKI-1 −6.13 −4.82 >−4.00RXF-393 >−4.00 >−4.00 >−4.00 SN12C >−4.00 >−4.00 >−4.00 TK-10 −6.42−5.79 >−4.00 UO-31 >−4.00 >−4.00 >−4.00 Prostate CancerPC-3 >−4.00 >−4.00 >−4.00 DU-145 >−4.00 >−4.00 >−4.00 Breast Cancer MCF7−6.17 >−4.00 >−4.00 MCF7/ADD-RES −4.10 >−4.00 >−4.00MDA-MB-231/ATCC >−4.00 >−4.00 >−4.00 HS 578T >−4.00 >−4.00 >−4.00MDA-MB-435 >−4.00 >−4.00 >−4.00 MDA-N >−4.00 >−4.00 >−4.00 BT-549−4.20 >−4.00 >−4.00 T-47D >−4.00 >−4.00 MG_MID −4.58 −4.17 −4.07 Delta2.31 2.18 1.54 Range 2.89 2.35 1.61

NSC: 675245

Panel/Cell Line Log₁₀ GI₅₀ Log₁₀ TGI Log₁₀ LC₅₀ LeukemiaCCRF-CEM >—4.00 >—4.00 >—4.00 HL-60(TB) >—4.00 >—4.00 >—4.00 K-562—5.17 >—4.00 >—4.00 MOLT-4 >—4.00 >—4.00 >—4.00RPMI-8226 >—4.00 >—4.00 >—4.00 SR >—4.00 >—4.00 >—4..00 Non-Small CellLung Cancer A549/ATCC >—4.00 >—4.00 >—4.00 EKVX >—4.00 >—4.00 >—4.00HOP-62 —4.29 >—4.00 >—4.00 HOP-92 >—4.00 >—4.00 >—4.00 NCI-H226 —6.01—5.44 >—4.00 NCI-H23 >—4.00 >—4.00 >—4.00 NCI-H322M >—4.00 >—4.00 >—4.00NCI-H460 —5.75 >—4.00 >—4.00 NCI-H522 —4.66 —4.34 —4.02 Colon CancerCOLO 205 >—4.00 >—4.00 >—4.00 HCC-2998 —5.32 >—4.00 >—4.00 HCT-116—6.16 >—4.00 >—4.00 HCT-15 >—4.00 >—4.00 >—4.00HT29 >—4.00 >—4.00 >—4.00 KM12 >—4.00 >—4.00 >—4.00 SW-620—5.38 >—4.00 >—4.00 CNS Cancer SF-268 >—4.00 >—4.00 >—4.00 SF-295—4.31 >—4.00 >—4.00 SF-539 >—4.00 >—4.00 >—4.00 SNB-19—4.53 >—4.00 >—4.00 SNB-75 —5.00 >—4.00 >—4.00 U251 —5.98 >—4.00 >—4.00Melanoma LOX IMVI >—4.00 >—4.00 >—4.00 MALME-3M >—4.00 >—4.00 >—4.00M14 >—4.00 >—4.00 >—4.00 SK-MEL-2 >—4.00 >—4.00 >—4.00SK-MEL-28 >—4.00 >—4.00 >—4.00 SK-MEL-5 —4.14 >—4.00 >—4.00 UACC-257—6.49 —6.04 >—4.00 UACC-62 —7.19 >—4.00 >—4.00 Ovarian Cancer IGROV1—4.17 —4.59 —4.13 OVCAR-3 —6.41 >—4.00 >—4.00 OVCAR-4—5.58 >—4.00 >—4.00 OVCAR-5 —6.11 >—4.00 >—4.00OVCAR-8 >—4.00 >—4.00 >—4.00 Renal Cancer 786-0 —4.17 >—4.00 >—4.00 A498—6.51 —6.05 —5.17 ACHN —4.24 >—4.00 >—4.00 CAKI-1 —6.57 —6.03 >—4.00RXF-393 —4.92 >—4.00 >—4.00 SN12C >—4.00 >—4.00 >—4.00 TK-10 —6.59—6.09 >—4.00 UO-31 >—4.00 >—4.00 >—4.00 Prostate CancerPC-3 >—4.00 >—4.00 >—4.00 DU-145 >—4.00 >—4.00 >—4.00 Breast Cancer MCF7—5.83 >—4.00 >—4.00 MCF7/ADR-RES >—4.00 >—4.00 >—4.00MDA-MB-231/ATCC >—4.00 >—4.00 >—4.00 HS 578T —4.06 >—4.00 >—4.00MDA-MB-435 >—4.00 >—4.00 >—4.00 MDA-N >—4.00 >—4.00 >—4.00BT-549 >—4.00 >—4.00 >—4.00 T-47D —4.80 >—4.00 >—4.00 MG_MID —4.67 —4.18—4.02 Delta 2.53 1.91 1.15 Range 3.19 2.09 1.17

NSC: 675244

Panel/Cell Line Log₁₀ GI₅₀ Log₁₀ TGI Log₁₀ LC₅₀ Leukemia CCRF-CEM —5.67—5.15 >—4.00 HL-60(TB) —5.61 >—4.00 K-562 —5.87 —4.48 >—4.00 MOLT-4—5.62 —5.12 >—4.00 RPMI-8226 —5.53 >—4.00 >—4.00 —5.39 Non-Small CellLung Cancer A549/ATCC —4.87 —4.58 —4.29 EKVX —4.60 —4.19 >—4.00 HOP-62—4.92 —4.53 —4.13 HOP-92 —4.96 —4.59 —4.20 NCI-H226 —5.65 —5.29 —4.41NCI-H23 —4.87 —4.51 —4.16 NCI-H322M —4.88 —4.55 —4.22 NCI-H460 —5.65—4.79 —4.39 NCI-H522 —5.28 —4.76 —4.37 Colon Cancer COLO 205 —5.50 —4.92—4.46 HCC-2998 —5.60 —4.94 —4.41 HCT-116 —6.42 —4.86 —4.41 HCT-15 —5.13—4.58 —4.10 HT29 —5.49 —4.88 —4.44 KM12 —5.20 —4.71 —4.34 SW-620 CNSCancer SF-268 —5.35 —4.24 >—4.00 SF-295 —4.82 —4.55 —4.27 SF-539 —4.77—4.48 —4.20 SNB-19 —4.99 —4.52 —4.06 SNB-75 —5.70 —5.19 >—4.00 U251—6.50 —4.86 —4.32 Melanoma LOX IMVI —5.25 —4.68 —4.11 MALME-3M —4.90—4.55 —4.19 M14 —4.94 —4.54 —4.14 SK-MEL-2 —4.78 —4.34 >—4.00 SK-MEL-28—4.88 —4.57 —4.26 SK-MEL-5 —5.47 —4.86 —4.43 UACC-257 —6.51 —6.07 —4.48UACC-62 —7.15 —4.97 —4.18 Ovarian Cancer IGROV1 —5.48 —4.81 —4.40OVCAR-3 —6.55 —5.10 —4.51 OVCAR-4 —5.80 —4.83 —4.22 OVCAR-5 —6.26 —4.88—4.12 OVCAR-8 —5.04 —4.52 —4.02 Renal Cancer 786-0 —5.22 —4.73 —4.36A8498 —5.85 —5.53 —5.20 ACHN —4.99 —4.66 —4.33 CAKI-1 —6.69 —6.15 —4.84RXF-393 —5.71 —5.09 >—4.00 SN12C —5.00 —4.65 —4.30 TK-10 —6.54 —6.05—4.60 UO-31 —4.81 —4.54 —4.27 Prostate Cancer PC-3 —4.92 —4.49 —4.06DU-145 —4.90 —4.60 —4.29 Breast Cancer MCF7 —6.32 —4.94 —4.36MCF7/ADR-RES HS 578T —5.14 —4.66 —4.27 MIDA-MB-435 —4.99 —4.48 >—4.00MDA-N —5.34 —4.71 —4.19 BT-549 —4.91 —4.51 —4.10 T-47D —4.95 —4.63 —4.32—5.42 —4.45 >—4.00 MG_(—MID) —5.43 —4.78 —4.25 Delta 1.72 1.37 0.96Range 2.55 2.15 1.20

NSC: 675346

Panel/Cell Line Log₁₀ GI₅₀ Log₁₀ TGI Log₁₀ LC₅₀ LeukemiaCCRF-CEM >—4.00 >—4.00 >—4.00 HL-60(TB) >—4.00 >—4.00 >—4.00 K-562—5.64 >—4.00 >—4.00 MOLT-4 >—4.00 >—4.00 >—4.00RPMI-8226 >—4.00 >—4.00 >—4.00 SR >—4.00 >—4.00 >—4.00 Non-Small CellLung Cancer A549/ATCC —4.26 >—4.00 >—4.00 EKVX —4.11 >—4.00 >—4.00HOP-62 —4.19 >—4.00 >—4.00 HOP-92 —4.73 —4.15 >—4.00 NCI-H226 —7.76—6.92 —5.98 NCI-H23 —4.84 —4.23 >—4.00 NCI-H322M —4.89 >—4.00 >—4.00NCI-H460 —6.60 >—4.00 >—4.00 NCI-H522 —4.48 >—4.00 >—4.00 Colon CancerCOLO 205 —5.32 >—4.00 >—4.00 HCC-2998 —6.63 6.15 —4.68 HCT-116—6.94 >—4.00 >—4.00 HCT-15 —4.73 >—4.00 >—4.00 HT29 >—4.00 >—4.00 >—4.00KM12 —4.49 >—4.00 >—4.00 SW-620 >—4.00 >—4.00 >—4.00 >—4.00 CNS CancerSF-268 —4.72 >—4.00 >—4.00 SF-295 —4.67 —4.16 >—4.00 SF-539—4.29 >—4.00 >—4.00 SNB-19 —4.66 —4.02 >—4.00 SNB-75 —4.86 —4.24 >—4.00U251 —7.24 —459 >—4.00 Melanoma LOX IMVI —4.71 >—4.00 >—4.00 MALME-3M—4.46 >—4.00 >—4.00 M14 —4.55 >—4.00 >—4 00 SK-MEL-2 —4.61 >—4.00 >—4.00SK-MEL-28 —4.35 >—4.00 >—4.00 SK-MEL-5 —4.33 >—4.00 >—4.00 UACC-257—7.58 —7.08 —6.51 UACC-62 <—8.00 —7.55 —4.07 Ovarian Cancer IGROV1 —6.79—6.25 >—4.00 OVCAR-3 —7.72 —4.67 >—4.00 OVCAR-4 —6.92 —4.57 >—4.00OVCAR-5 —7.35 —6.24 >—4.00 OVCAR-8 —5.35 >—4.00 >—4.00 SK-OV-3—4.90 >—4.00 >—4.00 Renal Cancer 786-0 —4.87 >—4.00 >—4.00 A498 —6.84—6.53 —6.03 ACHN —4.64 >—4.00 >—4.00 RXF-393 —4.79 —4.37 >—4.00SN12C >—4.00 >—4.00 >—4.00 TK-10 —7.20 —6.38 —4.27 UO-31 —4.45 >—4.00—4.00 Prostate Cancer PC-3 —4.21 >—4.00 >—4.00 DU-145—4.54 >—4.00 >—4.00 Breast Cancer MCF7 —6.09 >—4.00 >—4.00 MCF7/ADR-RES—4.88 —4.22 >—4.00 HS 578T —4.63 >—4.00 >—4.00 MDA-MB-435 —4.55—4.06 >—4.00 MDA-N >—4.00 >—4.00 >—4.00 BT-549 —4.00 >—4.00 >—4.00 T-47D—4.74 —4.39 —4.04 —5.77 >—4.00 >—4.00 MG_MID —5.17 —4.42 —4.13 Delta2.83 3.13 2.38 Range 4.00 3.55 2.51

NSC: 675345

Panel/Cell Line Log₁₀ GI₅₀ Log₁₀ TGI Log₁₀ LC₅₀ LeukemiaCCRF-CEM >—4.00 >—4.00 >—4.00 HL-60(TB) >—4.00 >—4.00 >—4.00 K-562—4.51 >—4.00 >—4.00 MOLT-4 >—4.00 >—4.00 >—4.00RPMI-8226 >—4.00 >—4.00 >—4.00 SR >—4.00 >—4.00 >—4.00 Non-Small CellLung Cancer A549/ATCC EKVX >—4.00 >—4.00 >—4.00HOP-62 >—4.00 >—4.00 >—4.00 HOP-92 —4.32 >—4.00 >—4.00 NCI-H226 —4.84—4.26 >—4.00 NCI-H23 —6.24 —5.61 —5.07 NCI-H322M —4.66 >—4.00 >—4.00NCI-H460 >—4.00 >—4.00 >—4.00 NCI-H522 —6.09 >—4.00 >—4.00—4.07 >—4.00 >—4.00 Colon Cancer COLO 205 —4.47 >—4.00 >—4.00 HCC-2998—5.63 —5.16 —4.13 HCT-116 —5.39 >—4.00 >—4.00HCT-15 >—4.00 >—4.00 >—4.00 HT29 >—4.00 >—4.00 >—4.00KM12 >—4.00 >—4.00 >—4.00 SW-620 —4.42 >—4.00 >—4.00 CNS CancerSF-268 >—4.00 >—4.00 >—4.00 SF-295 —4.41 >—4.00 >—4.00SF-539 >—4.00 >—4.00 >—4.00 SNB-19 —4.50 >—4.00 >—4.00 SNB-75—4.28 >—4.00 >—4.00 U251 —5.64 —4.67 —4.05 Melanoma LOXIMVI >—4.00 >—4.00 >—4.00 MALME-3M >—4.00 >—4.00 >—4.00M14 >—4.00 >—4.00 >—4.00 SK-MEL-2 —4.11 >—4.00 >—4.00SK-MEL-28 >—4.00 >—4.00 >—4.00 SK-MEL-5 >—4.00 >—4.00 >—4.00 UACC-257—5.86 >—4.00 —5.24 UACC-62 —6.46 —5.55 >—4.00 Ovarian Cancer IGROV1—5.36 —4.64 >—4.00 OVCAR-3 —5.66 >—4.00 —5.39 OVCAR-4 >—4.00 >—4.00OVCAR-5 —5.81 —5.27 >—4.00 OVCAR-8 >—4.00 >—4.00 >—4.00 SK-OV-3—4.26 >—4.00 >—4.00 Renal Cancer 786-0 —4.96 >—4.00 >—4.00 A498 —6.32—5.81 —5.39 ACHN —4.11 >—4.00 >—4.00 CAKI-1 —4.49 >—4.00 >—4.00RXF-393 >—4.00 >—4.00 >—4.00 SN12C —6.59 —5.78 >—4.00TK-10 >—4.00 >—4.00 >—4.00 UO-31 Prostate CancerPC-3 >—4.00 >—4.00 >—4.00 DU-145 >—4.00 >—4.00 >—4.00 Breast Cancer MCF7—6.14 —5.25 >—4.00 MCF7/ADR-RES >—4.00 >—4.00 >—4.00 MDA-MB-231/ATC—4.74 >—4.00 >—4.00 HS 578T —4.17 >—4.00 >—4.00 MDA-MB-435—4.23 >—4.00 >—4.00 MDA-N >—4.00 >—4.00 >—4.00BT-549 >—4.00 >—4.00 >—4.00 T-47D —4.10 >—4.00 >—4.00 MG_MD —4.75 —4.21—4.07 Delta 2.03 1.61 1.32 Range 2.59 1.81 1.39

EXAMPLE 54 Inhibition of Protein Kinase C

The Protein Kinase C (PKC) screening assay utilized in the followingexperiments is similar to standard PKC assays used by manyinvestigators. Its primary features are that 1) the assay utilizes a50:50 mixture of recombinant mouse PKC α and mouse PKCβ₂; 2) employshistone as phosphate-accepting substrate; and 3) the PKC enzymaticactivity is activated with phosphatidylserine, TPA and low concentrationof calcium, so that both calcium and TPA are somewhat limiting for theextent of activation. In this manner the assay is sensitive toinhibitors of PKC activation. A more detailed description of the assayis provided in the following paragraphs.

The recombinant PKC formulation is a mixture (equal parts by activity)of mouse PKC∝ and mouse PKCβ₂. The enzymes are expressed in Sf9 insectcells from recombinant baculovirus and partially purified onDEAE-cellulose and Sephacryl 200 gel filtration. Sufficient PKC is addedto each reaction to provide approximately 4 pmols phosphate transferredin 30 minute (per total reaction). The reaction is linear over the timewhen 4 pmols of phosphate is transferred and the reaction remains linearwell beyond this time frame.

The PKC screening assay is performed in 96 well polystyrene U bottommicro titer plates, in a total reaction volume of 50 μL. Solutionmanipulations are performed during the assay utilize a Rainin, motorizedEDP-plus M8 eight-channel micropipettor.

Samples were typically assayed at three dilutions, however some highlyactive pure compounds were assayed at six dilutions. Assay samples aredissolved in DMSO at a concentration of 10 mg/mL or less for samplessuspected of being more potent. In some cases 50% DMSO:water, water, ormethanol is substituted (if essential) for the solvent. At least 25 μLof the highest concentration sample to be assayed is transferred to awell in a 96 well U-bottom polystyrene assay plate. Serial 5-fold or10-fold dilutions (depending on the dose-range desired) are made usingthe EDP-plus M8 eight-channel pipettor in dilute mode and mixing byrepipetting. Using the 8-channel pipettor, 2 μL of each dilution istransferred to the appropriate wells of the plate(s) to be used for eachassay. Duplicate assays are performed for each dose, with each assay,allowing six wells (half the row) for three-dose assays, or 12 wells(the whole row) for six-dose assays. In general, extracts and fractionsare assayed at three doses: 400, 40 and 4 μg/mL, while pure compoundsare tested at six doses: 400, 80, 16, 3.2, 0.64, 0.128 (8-fold series).The results of these experiments are shown in Table 2. TABLE 2Inhibition of Protein Kinase C Compounds, NSC# Structure IC₅₀ (μg/ml)675347

1 × 10⁰ 675346

5 × 10⁻¹ 675345

9 × 10⁻¹ 675344

5 × 10¹ 675343

3 × 10¹ 676628

1 × 10⁰ 676629

2 × 10⁻¹ 676630

9 × 10⁻¹ 676631

2 × 10⁰ 676632

5 × 10¹ 676633

6 × 10⁰ 676634

8 × 10⁻¹ 676635

8 × 10⁰ 674973

7 × 10⁰ 675244

1 × 10⁰ 675245

1 × 10⁰ 675246

3 × 10⁰ 675247

1 × 10¹

1. A method for treating a patient having a tumor, said methodcomprising the step of administering to the patient an effective amountof a compound of the formula

wherein R₁ and R₂ are independently selected from the group consistingof

H, CHO, CH₂OH, and CH₂NH₂; and X and Y are independently selected fromthe group consisting of Se, S, O, NR, and NH, where R is H or C₁-C₇alkyl; R₃, R₄, R₅, and R₆ are each independently selected from the groupconsisting of H, CHO, CH₂OH, and CH₂NH₂; and when any one of R₁, R₂, R₃,R₄, R₅, and R₆ is CH₂NH₂, the pharmaceutically acceptable salts thereof;with the proviso that R₁ and R₂ are not both


2. The method of claim 1 wherein the administering step includes thecompound where R₁ and R₂ are each H.
 3. The method of claim 1 whereinthe administering step includes the compound where R₃ and R₆ are eachindependently selected from the group consisting of CHO, CH₂OH, andCH₂NH₂.
 4. The method of claim 3 wherein the administering step includesthe compound where R₁ and R₂ are each H.
 5. The method of claim 1wherein the administering step includes the compound where at least oneof R₁ and R₂ is selected from the group consisting of CHO, CH₂OH, andCH₂NH₂.
 6. The method of claim 1 wherein the administering step includesthe compound where at least one of R₁, R₂, R₃, R₄, R₅, and R₆ isselected from the group consisting of CHO, CH₂OH, and CH₂NH₂.
 7. Themethod of claim 1 wherein the administering step includes the compoundwhere one of R₁ and R₂ is selected from the group consisting of


8. The method of claim 7 wherein the administering step includes thecompound where at least one of R₃, R₄, R₅, and R₆ is selected from thegroup consisting of CHO, CH₂OH, and CH₂NH₂.
 9. The method of claim 7wherein the administering step includes the compound where each of R₃,R₄, and R₆ is H.
 10. The method of claim 7 wherein the administeringstep includes the compound where the other of R₁ and R₂ is selected fromthe group consisting of CHO, CH₂OH, and CH₂NH₂.
 11. The method of claim7 wherein the administering step includes the compound where X is Se.12. The method of claim 1 wherein the administering step includes thecompound where one of R₁ and R₂ is


13. The method of claim 12 wherein the administering step includes thecompound where the other of R₁ and R₂ is selected from the groupconsisting of CHO, CH₂OH, and CH₂NH₂.
 14. The method of claim 12 whereinthe administering step includes the compound where the R₅ is selectedfrom the group consisting of CHO, CH₂OH, and CH₂NH₂.
 15. The method ofclaim 12 wherein the administering step includes the compound where X isSe.
 16. The method of claim 1 wherein the administering step furthercomprises a pharmaceutically acceptable carrier therefor.
 17. The methodof claim 1 wherein the administering step includes the compound as acomplex with a cyclodextrin.
 18. A process for preparing an intermediatecompound of the formula

the process comprising the step of reacting a compound of the formula

with a compound of the formula

in the presence of sodium cyanide and dimethylformamide; wherein X and Yare independently selected from the group consisting of Se, S, O, NR,and NH, where R is H or C₁-C₇ alkyl; and R₁, R₂, R₃, R₄, and R₆ are eachindependently selected from the group consisting of H, CHO, CH₂OH, andCH₂NH₂.
 19. A process for preparing a compound of the formula

the process comprising the step of reacting a compound of the formula

with a compound of the formula

in the presence of sodium cyanide and dimethylformamide to form anintermediate of the formula

wherein X, Y, and Z are each independently selected from the groupconsisting of Se, S, O, NR, and NH, where R is H or C₁-C₇ alkyl; and R₁,R₂, R₃, R₄, and R₆ are each independently selected from the groupconsisting of H, CHO, CH₂OH, and CH₂NH₂.
 20. The process of claim 19further comprising the step of reacting the intermediate of the formula

with RNH₂Cl in the presence of NaOAc, when Z is NR; with (CH₃CO)₂O inthe presence of HCl, when Z is O; with [(C₆H₁₁)₃Sn]₂S in the presence ofBCl₃, when Z is S; or with [(C₆H₁₁)₃Sn]₂Se in the presence of BCl₃, whenZ is Se.
 21. The process of claim 20 wherein R₁, R₂, R₃, R₄, and R₆ areeach H.
 22. The process of claim 21 further comprising the step ofreacting the compound of the formula

with (a) base, and (b) dimethylformamide, to form a compound of theformula

wherein R₁ is selected from the group consisting of H and CHO.